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Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

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† School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
§ Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
∥ Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
⊥ Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
# CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
Medicines for Malaria Venture, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland
α Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
β Department of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States
γ Department of Chemistry, Lawrence University, 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911, United States
δ Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, U.K.
ϵ Research School of Biology, The Australian National University, Canberra, ACT 2601, Australia
ζ Asclepia Outsourcing Solutions, Damvalleistraat 49, B-9070 Destelbergen, Belgium
η Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
θ Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, U.K.
ι European Molecular Biology Laboratory—European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
κ Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland
λ Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria 3010, Australia
μ IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, EH8 9XD, U.K.
ν Cambridge MedChem Consulting, 8 Mangers Lane, Duxford, Cambridge CB22 4RN, U.K.
ξ School of Chemistry, The University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
π Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland
*E-mail: [email protected], @mattoddchem
Cite this: ACS Cent. Sci. 2016, 2, 10, 687–701
Publication Date (Web):September 14, 2016
https://doi.org/10.1021/acscentsci.6b00086

Copyright © 2016 American Chemical Society. This publication is licensed under CC-BY.

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Abstract

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The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

Synopsis

Starting from hits identified by a pharmaceutical company, new antimalarials have been discovered using an “open source” approach that discloses data in real time and eschews secrecy.

Introduction

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Malaria remains one of the world’s most deadly diseases. There were an estimated 214 million cases of malaria in 2015, including around 438,000 deaths of which the majority, tragically, were young children. (1) Besides the threat to human health, there is significant economic and social impact on the affected communities with malaria costing Africa billions of dollars per annum in direct losses and even more when considering lost economic growth. (2, 3)
The continual threat of drug resistance has led to the World Health Organization (WHO) recommending that all treatments should only be used in combination; artemisinin combination therapies (ACTs) comprising an artemisinin derivative and a 4-aminoquinoline or amino alcohol currently represent the front line. However, the inevitable reports of resistance or tolerance, in the form of increased parasite clearance times, have already appeared. (4-6) Loss of the artemisinin class of drugs is a terrifying scenario that requires urgent risk mitigation. Apart from the introduction of the ACTs, no viable new drug for malaria has entered the market in the past 15 years, and the recent results of the Mosquirix vaccine phase III trials showed 18–36% efficacy depending on patient age and other factors. (7, 8) New chemical series that can replace and complement the ACTs are urgently needed and are being sought by a combination of academic and industrial groups, sometimes in collaboration with nongovernmental organizations (NGOs). (9-11) Of particular interest are lead candidates with differentiated activity profiles, ideally targeting gametocyte or liver stage parasites in addition to blood stages. (12-15)
The ability of the pharmaceutical industry to provide new medicines cost-effectively is diminishing. (16) The industry acknowledges that lack of innovation is a problem. (17) Pharma is responsible for the creation of most marketed drugs, yet many of these are arguably not innovative; in contrast academia and the biotech industry generate more innovative leads, but many are orphan drugs. (18) Such challenges disproportionately affect research into new medicines for tropical diseases, which would inevitably generate a slim profit margin unlikely to recoup the necessary expenses of research and development. (19)
The weak status of many drug development pipelines in the pharmaceutical industry is driving the exploration of alternative models. The current model of drug discovery, whether in academia (20) or industry, can generally be characterized by secrecy and an underlying profit motive. (21) In the area of tropical diseases there are significant philanthropic efforts being made by many companies in providing treatments (22) and engaging in drug development (23) but also in conducting not-for-profit research. (24, 25) There have been calls for greater sharing of data in the NTD field, (26, 27) including the development of patent pools (28) and new Product Development Partnerships. (29) Repositioning of existing drugs is seen as a possible general strategy for the development of new antimalarials, even though the challenges of such an approach are clear. (30) There has been much recent discussion of the need for “Open Innovation”, a term with a nebulous definition but typically describing a range of ideas from the sharing of data in a precompetitive environment through to competitions that allow organizations to bring in the best external ideas to complement in-house research but for which there is no requirement for any collaboration. (31)
A model that has been mooted, (32-38) but never properly implemented and evaluated, is drug discovery and development where all data and ideas are freely shared, there are no barriers to participation, and there are no patents—so-called “Open Source” Drug Discovery. The requirement for total sharing of data as well as workflows in drug discovery and development (i.e., the experimental science, as opposed to the software used in the project (39)) would mirror the same practices in open source software development—a model that has created robust and successful products in widespread use and formed the foundation of major industries as well as spawning for-profit open source software companies. It was shown recently that the opening up of a laboratory-based chemical research project to unrestricted participation by anyone accelerated the research because experts unknown to the core team were able to join the project and solve transient project needs. (36) That project involved the discovery of a new synthetic route to a known compound, specifically the active enantiomer of the drug of choice for the treatment of schistosomiasis, praziquantel. (40) The project benefited from the open sharing of chemical data and procedures on the Internet, i.e., using the Internet as a medium that facilitated collaboration and peer review where participants could influence the direction of the research before it occurred, rather than use the online content merely as an information resource. Several other initiatives have leveraged the advantage of open online discussion of chemical data and results generated by others. (41-43)
The present work extends this idea to the identification of novel bioactive compounds. A previous demonstration of an open drug discovery cycle was shown by the Usefulchem project, which found four micromolar hits from a small product library after in silico target prediction and docking. (44) The Open Source Drug Discovery project in India has carried out a crowdsourcing project for annotation of the Mycobacterium tuberculosis genome. (45-47) In the field of biotechnology the CAMBIA organization used patents to enforce a code of conduct based on the open sharing of technologies, in that experimental tools could be freely used, provided no further patents were taken to restrict the use of those tools by others. (48)
The “open source” moniker is not merely semantic and distinguishes such projects from other “open” ventures in several important regards, (38) described by the six laws that governed the operation of the present project (Figure 1, Figure S1). (49) Crucially, the research process (i.e., strategic discussions, issues involving doubt) takes place in the public domain. The Creative Commons license covering project content ensures free reuse of all content including for commercial purposes (CC-BY), (50) and uses a free or open source composite technical platform that has recently been reviewed. (51, 52)

Figure 1

Figure 1. Six laws of open research governing the present project.

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In recent years, teams led by Novartis, St. Jude’s Children’s Research Hospital, and GlaxoSmithKline (GSK) Tres Cantos have released large data sets of antimalarial compounds derived from phenotypic high throughput screening (HTS) campaigns. (53-56) The GSK Tres Cantos Antimalarial (TCAMS) data set contained 13,533 filtered hits which were subsequently prioritized and grouped to provide numerous starting points for other research groups; (57) all of these 47 scaffolds have been explored either internally by GSK, by independent groups, or in collaboration between GSK and academic groups. GSK themselves have published evaluations of two of these priority series, the cyclopropyl carboxamides (58, 59) and an indoline series. (60) No further optimization work has been performed by GSK on these two series due to the inherent risks identified. The original GSK data set was used to identify starting points for the present campaign, resulting in the selection of TCMDC-123812 (OSM-S-5, Figure 2A) and its 4-aminoantipyrine derivative TCMDC-123794 (OSM-S-6) because of their attractive physicochemical properties, such as low logP and molecular weight, coupled with promising bioactivity and therefore presumed high ligand efficiency. (Compound numbering in this paper is based on the original project numbering, rather than a renumbering for this paper, allowing simpler cross-correlation between this paper and the live Web sites. The convention used is Open Source Malaria (OSM)-first letter of city in which compound was first made (e.g., S = Sydney)-incremental integer. Batch numbers are included in internal project numbering schemes.) A number of compounds in the original TCAMS set (53) featured the arylpyrrole core with alternative head groups lacking the ester linkage (Figure 2B). TCMDC-123563 was discounted (Figure S2) (61) as it represented a singleton and contained an unfavorable ketone linkage. A cluster of related compounds, the 2-iminothiazolidin-4-ones (the “near neighbors”, NN), was targeted because the members (including TCMDC-124103, -125697, and -125698) possessed promising activities without the ester, and indicated tolerance to variation elsewhere in the structure. While this work was being written up for publication, Gilbert et al. published details of a series of pyrrolones (identified through an unpublished screen performed by the World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO-TDR) but also identified in the Novartis antimalarial data set (55)) that have some structural similarities to the NN compounds (i.e., an arylpyrrole joined through a double bond to a different heterocycle), and comparisons will be drawn below with this series. (62, 63)

Figure 2

Figure 2. (A) Arylpyrrole hits from the TCAMS data set. (B) Selected “near neighbors” (NN) from the TCAMS data set. Activities quoted are vs 3D7. Not shown: related NN compounds TCMDC-124456 (680 nM) and TCMDC-125659 (237 nM). (XC50 = approximate IC50 value. (53))

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It was important to resynthesize the original hit compounds (Figure 2A) to confirm their activity with authentic samples prior to beginning a hit to lead campaign where the NN compounds would act as a potential backup subseries.

Results and Discussion

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Resynthesis of Original Hits and Their Putative Prodrug Fragments

The synthetic approaches to any molecule in this paper may be found in full in the relevant electronic laboratory notebook (64) and are summarized in the Supporting Information (Chemical Protocols; figures with the prefix “SC” may be found therein).
The two original GSK hits (OSM-S-5 and -6) were successfully resynthesized via a novel pyrrole acid (OSM-S-4, Figure SC1) that was prepared via a Paal–Knorr cyclization of the relevant aniline and ethyl 2-acetyl-4-oxopentanoate. (65, 66) This approach was found to be superior to an alternative method involving initial synthesis of the unfunctionalized N-arylpyrrole, followed by conversion to the corresponding aldehyde with a Vilsmeier–Haack reaction (a procedure that was improved through a community suggestion (Figure S3) (67)) and then oxidation to a carboxylic acid, because the pyrrole aldehyde was found to be remarkably resilient to a range of oxidants. (An alternative route using a Friedel–Crafts acylation between the unsubstituted pyrrole and ethyl chloroformate, suggested in an e-mail from the community, gave only starting material in two attempts.)
To confirm the promise of the two starting points OSM-S-5 and -6, they were evaluated against 3D7 (drug-sensitive) and K1 (chloroquine resistant) strains of Plasmodium falciparum in a whole cell assay and against HEK-293 cells as a cytotoxicity marker (Table SB1, Biological Protocols; tables with the prefix “SB” may be found in the Supporting Information). Biological data may be browsed in a static data set taken as a snapshot for this paper (Data Sets S1 (Excel), S2 (SDF)), online in a database constructed through periodic batch uploads, (68) or in a “living database” to which may be added future data; (69) the latter may be visualized in a web browser (70) using an open source system that was recently deployed in the Wikipedia Chemical Structure Explorer, (71) or the data may be downloaded and visualized offline with proprietary (Figure S4) (72) or open source (Figure S5) (73) tools). The evaluation was performed in three different institutions using different assays and widely employed controls; controls are important to assess reproducibility and interassay variability (74) but also to minimize possible bias in evaluating compounds where there are pre-existing data from other researchers already in the public domain (Figure S6). (75) The tests confirmed that the original compounds TCMDC-123812 (OSM-S-5) and TCMDC-123794 (OSM-S-6) are potent (300–500 nM range), although slightly less than previously reported (IC50 of ca. 330 and 54 nM respectively from a colorimetric LDH assay over 72 h (53)) with low associated cytotoxicities and similar efficacy against 3D7 and K1 strains. The stability of the ester linker under biologically relevant conditions was expected to be poor, so the aldehyde, ethyl ester, and carboxylic acid 4-fluoropyrroles made en route to these compounds were evaluated as potentially active fragments but were found to exhibit relatively low activity, suggesting that the parent compounds do not act as prodrugs in this way (similar inactivity was observed for the 4-H, 4-Me, and 4-CF3 aldehydes, esters, and acid fragments) (Data Sets S3–S5).

Amide Analogues of the Original Hits

Replacement of the ester with a hydrolytically more stable amide was undertaken through synthesis of eight derivatives (Figure 3), most of which were obtained through SOCl2-mediated conversion of acid OSM-S-4 to the acid chloride. Compound OSM-S-16 served as a control lacking the pyrrole moiety, OSM-S-8 served as a truncated “des-glycinyl” analogue, and the importance of amide methylation was explored with compounds OSM-S-59 and -93. In addition, the six most relevant commercially available compounds were purchased (Figure SC2). (For more on strategies for selecting compounds for commercial acquisition, colloquially known as “SAR by catalog”, see the Supporting Information (Text S2 and the component files referred to therein).)

Figure 3

Figure 3. Synthesized amide analogues. Synthetic details and structures of purchased compounds may be found in the Supporting Information. All compounds were found to possess low activity (Table SB2).

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The conversion of ester to amide resulted in essentially total loss of biological activity in all cases (Table SB2), even for the analogues involving minimal changes (OSM-S-19 and OSM-S-21), so the amide series was not explored further.

The Alternative “Near Neighbor” 2-Iminothiazolidinones

In parallel with the initial evaluation of the amide analogues, a number of NN analogues were synthesized (Figure 4), typically from a Vilsmeier–Haack oxidation of the relevant pyrrole to the corresponding aldehyde and then condensation with the appropriate 2-iminothiazolidin-4-one (Figure SC3). (76-78) While double bond geometry was undefined for the original hits, Z-geometry was established here by X-ray crystallography on four compounds and therefore assumed more broadly for the series (Figure SC4). Given the low predicted solubility of these NN compounds, several were generated with lower clogP values and submitted for biological testing (OSM-S-109 through -115, OSM-S-108, and OSM-S-138), alongside analogues synthesized and submitted by an independent undergraduate laboratory cohort: OSM-A-1 through -4 and resyntheses of OSM-S-37 and -111.

Figure 4

Figure 4. Near neighbor compounds biologically evaluated. Raw data may be found in Table SB3.

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Many compounds in the NN series showed high potencies (shown schematically in Figure 4; raw data in Table SB3), with several found to be more active than the original TCAMS hits. The compounds exhibited low associated cytotoxicity. The aryl component of the pyrrole moiety was moderately tolerant to changes (though small changes could result in large changes in activity, exemplified by the 4-F and 3-F isomers), while the thiazolidinone component was found to be more sensitive. Incorporation of cyclopentyl, phenyl, and acetyl components was tolerated, but the methylenenitrile group was not. Replacement of the arylpyrrole moiety with a phenyl resulted in loss of activity.
While high potency was obtained with several members of the NN series, this was achieved at the cost of high calculated lipophilicity with many compounds in this series exhibiting calculated logP values of 5 or more and correspondingly poor lipophilic efficiency (Figures S15 and S16). (79) Solubility was a challenge in several of the assays examining these compounds. Those compounds with more polar groups on the constituent aromatic rings suffered a drop in potency, but the pyridinyl analogue OSM-S-51 (calculated LogP = 1.8) provides a possible future line of inquiry for the community. A lipophilicity/potency trend was also generally seen in the pyrrolone series, (62) though potency was seen for several compounds containing a substituted piperidine ring in place of the N-aryl group. (63)
The open nature of the project enabled regular consultation with the wider medicinal chemistry community in real time, i.e., where community input could influence the direction of the research. An important contribution to the project from outside the core experimental team (Figure S17) (80) was discussion of whether the most potent members of the NN series were pan assay interference compounds (PAINS), i.e., compounds frequently appearing as hits in high throughput screens yet which do not exhibit a straightforward “drug-like” interaction with a biological target. (81) The OSM compounds were run through the KNIME PAINS filter, (82, 83) and both the 2-imino-4-thiazolidinone and arylpyrrole components of these compounds were flagged as potential PAINS, with the proposed cause of the interference of the former being the thiazolidinone exo-double bond acting as a Michael acceptor, though it has been noted that this core is much more problematic in rhodanines than in their 2-imino counterparts. (84) The topic of PAINS has been the subject of extensive recent discussion in papers (84-88) and in online communities (Figures S18 and S19). (89, 90) Although most concern has centered on rhodanines, any related structure could be problematic if it contains a potentially reactive conjugated exo-double bond. In the area of chemotherapeutic and antiparasitic agents, such motifs may still be present in viable leads. (84) The negative view of rhodanine derivatives in the medicinal chemistry community is generally derived from academic reports and patents where positive assay hits have been reported without adequate evaluation of SAR or elucidation of the mode of action. A complicating factor, often not considered, is that PAINS are defined on the basis of results from target-based screens, where one would not link a cellular readout to the target if nonspecific protein reactivity were possible. (84) Conversely, a covalent modifier from a cellular screen may still be useful as a probe under some circumstances. (91) The present compounds may not be problematically reactive and may still be progression candidates for the following reasons: (1) The parent hit compounds (TCMDC-123812 (OSM-S-5) and -123974 (OSM-S-6), Figure 2) were shown not to be “promiscuous” frequent hitters in the original GSK data; (53) (2) the assay data described above show that the relevant 2-imino-4-thiazolidinone fragment was inactive on its own (OSM-S-55, Table SB3, entry 30), and (3) preliminary experimental controls were performed to assess the reactivity of the exo double bond (Figure SC5) that showed no reactivity of the exocyclic double bond to hydrogenation or the addition of hydride or a thiol in model cases. Yet it was noted that these compounds not only are closely related to known PAINS but also fail by ALARM NMR filtering, which is designed to detect known protein-reactive cores. (92-94) Ultimately, the authorship team adopted varying positions. Overall, given the poor physical properties of these compounds and the extensive additional work that would be needed to fully mitigate the series risks, and encouraged by one of us (J.B.B.) to move away from PAINS-like structures, the team decided not to further pursue this subseries.
Poor solubility with excessive lipophilicity may not just impart poor pharmacokinetic properties but also drive nonspecific protein reactivity through hydrophobic burial that may not be picked up in in vitro assays. The emphasis for this series moved toward analogues that promised improved solubility. As with all key strategic decision points in this open source project, discussion of possible structures took place in an online public consultation. (95) The meeting recalibrated the project focus with selection of the next synthetic compounds and agreement on which commercially available analogues to purchase and evaluate (Figure S24). (96) This community consultation confirmed ethers, amines, sulfonamides, oxadiazoles, and substituted ester analogues of the original arylpyrrole hits as the most valuable targets (Figure S25). (97) Synthesis of a shortlist of such analogues was planned and undertaken by whomever wished to do so (half of the ten top-ranked synthetic shortlist were ultimately made; synthetic planning assistance was received gratis from the private sector (Supporting Information, Texts S6 and S7), and the most relevant commercially available compounds were purchased and evaluated. GSK assessed the proposed compounds and confirmed (publicly) that none of the molecules had previously been evaluated for antimalarial activity as part of the TCAMS screen.

Analogues in the Arylpyrrole Series

Several analogue series of the original arylpyrroles were synthesized and evaluated (Figure 5, raw data in each case may be found in the Supporting Information).

Figure 5

Figure 5. Analogues evaluated in the main arylpyrrole series.

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Ethers
One of the most promising proposed analogues was the ether OSM-S-236. A number of approaches have failed to generate the desired product, attributed to the instability of either the arylpyrrole alcohol starting material OSM-S-11 (which decomposed on silica and when stored under inert conditions at 2 °C) or (if formed) the desired product itself (Figure SC6). The synthesis of this compound was abandoned, given that similar side reactivity may be seen in vivo, although such reactivity could be mitigated through the use of more electron-deficient pyrroles.
Amines
Four amine analogues (OSM-S-58, -60, -94, and -95) were successfully prepared by reductive alkylation of the relevant pyrrole aldehyde, and three additional amine analogues were purchased (OSM-S-88 to -90, Figure SC7). All were found to be inactive. The synthesized structures were found to be prone to decomposition under ambient conditions.
Modified Esters
In an attempt to decrease the hydrolytic lability of the ester, methyl groups were introduced adjacent to this functional group (OSM-S-116 and -68) (Figure SC8). To assess the influence of introducing methyl groups to the terminal amide, analogues OSM-S-82 and OSM-S-91 were purchased. All compounds were found to exhibit low potency (Table SB4), further suggesting that minor structural changes to the potent TCAMS hit compounds reduce activity.
Ketones
Friedel–Crafts acylation of a pyrrole precursor with succinic anhydride and subsequent amidation provided three ketone analogues (OSM-S-98, -102, and -103, Figure SC9) that were found to exhibit essentially zero potency, with only OSM-S-103 showing any activity at higher concentrations.
Sulfonamides
Three sulfonamide analogues (OSM-E-1 to -3) were synthetically derived directly from the relevant arylpyrrole (Figure SC10) and were also found to lack potency.
Pyrazoles
Two pyrazole analogues (OSM-S-57 and -92) were synthesized (Figure SC11) and evaluated to assess the impact of modifying the arylpyrrole core. Both compounds were found to be inactive; the fluoro analogue of OSM-S-57 was thus not synthesized. A related heterocycle alteration was also found to be detrimental to the literature pyrrolone series. (62)
Oxazoles
The oxazole analogue OSM-S-105 was prepared from the carboxylic acid of the corresponding arylpyrazole, though the analogous sequence for the parent arylpyrrole series could not be completed (Figure SC12). This compound and several of the synthetic precursors were evaluated and all found to be inactive.
Triazoles
The triazole analogue OSM-E-8 was synthesized via a Cu(I)-catalyzed cycloaddition reaction (Figure SC13) and evaluated alongside four synthetic precursors and side products, but all compounds were found to be inactive.

Synthetic Threads That Remain Open

Several synthetic targets for this series remain open (Figure 6) such as the ether compound OSM-S-236 (though it seems likely that this compound will be unstable) and the oxazole OSM-S-246. The oxadiazole shown was proposed, and preliminary experiments toward its synthesis were performed (see precursor OSM-S-269 in the project laboratory notebooks for further details). (64) The oxadiazole is a common replacement for carbonyl containing compounds in hit to lead campaigns, (98) and so it was reasoned that the inclusion of this heterocycle might have favorable consequences for drug metabolism, though a commercial oxadiazole analogue (OSM-S-85, Supporting Information) had been found to be inactive, leading to the synthetic effort toward the oxadiazole being downgraded. The tolerance of the NN set to the introduction of the pyridine in OSM-S-51 (Figure 4) could be explored further as a means to increase solubility in that cluster, and a pendant substituted piperidine was found to lead to several potent compounds in the pyrrolone series that possesses some structural similarities to the NN series. (63) Indeed variation of the aromatic group in the arylpyrrole series was not explored given the intractability of substituting the ester: given the tight SAR, low solubility, and poor metabolic stability observed for the series, the project viewed the probabilities of success as limited and so did not pursue these targets.

Figure 6

Figure 6. Three targets that remain open for synthetic inquiry.

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In silico pharmacophore modeling has to date proven ineffective at high-confidence analogue prediction, but this remains an open challenge (99) to which others may contribute given the data set available. (68, 69) Some preliminary results suggesting a common feature map for the arylpyrrole and NN subseries were of particular interest and could be explored with the more substantial bioactivity data now available.
Along these lines, an automated bioisosteric replacement analysis (100) was performed for the NN series (Text S8, Data Set S19) focusing on replacement of the pyrrole phenyl substituent, and output suggestions were generated for potent compound OSM-S-35 (Figures S27–S30); these may be explored in the future.
All these structures are available for investigation by the community, building on the unsuccessful attempts detailed in the online laboratory notebooks. It is hoped that the sharing of negative synthetic data in this way (16 attempts in the case of the ether OSM-S-236) will lead to a faster completion of syntheses of analogues in the future since prior attempts are not “orphaned” in undisclosed or unpublished notebooks. Participants in future work may be physically located anywhere; they are requested (but not obligated) to operate open source (unrestricted sharing of all data and ideas) to avoid wasteful duplication of effort. The results, whether substantial or incremental, may be added to the series wiki. (101) However, it is important to acknowledge the limitations of the series identified to date, meaning further analogue synthesis undertaken by the community in the absence of better knowledge of the biological target is likely to be unproductive.

Advanced Biological Evaluation

To assess further the attractiveness of this class of compounds, attention was focused on the most potent of the newly discovered analogues and the original hits. Given that the compounds arose from a phenotypic assay, no mechanism of action (MoA) was known, and preliminary investigations described below were designed to probe this, with a view to minimizing any potential MoA overlap with other compounds already in development.

Metabolic and Solubility Assays

The two original GSK hits (OSM-S-5 and -6) and six NN compounds were evaluated for their kinetic solubility in phosphate buffer and their metabolic stability in human liver microsomes (Table SB5, Data Sets S20 and S21). Both the arylpyrrole esters showed good solubility, but showed degradation in microsomes even in the absence of cofactors for cytochrome P450 and glucuronidation enzymes (NADPH and UDPGA, respectively) suggesting degradation by nonspecific enzymes. The iminothiazolidinone (NN) compounds showed generally low rates of metabolic degradation but at a cost of very low solubility (a general feature also of the literature pyrrolone series (62) that displayed typically higher rates of metabolic clearance).

Oral Efficacy in Mice

Representative compounds from both subseries were evaluated in an oral in vivo mouse trial (Data Set S22). The original starting points OSM-S-5 and -6 (Figure 2) were chosen along with NN representative OSM-S-35 (Figure 4). All three compounds were found to be inactive in vivo in Plasmodium berghei ANKA infected mice at 50 mg/kg after 4 days po. It is plausible that at least some of the arylpyrrole ester compounds would be degraded by general hydrolysis during absorption, and this could explain their inactivity in the mouse model despite their more favorable (although still high) cLogP values. Analysis of the plasma samples from the trial with OSM-S-5 showed that the compound was indeed orally available, but concentrations in the blood were above the EC50 for only approximately 4 h (Data Set S23). The same compound was evaluated for stability in human and mouse plasma and found to be susceptible to hydrolysis (t1/2 114 min), but it was stable in human plasma with no measurable loss after 240 min (Data Set S24). Esterase activity is higher in rodents than in other species, (102) as confirmed by using p-nitrophenol acetate as a control compound in this assay. By way of comparison, the literature pyrrolone series had also exhibited low oral bioavailability that likely resulted from a combination of low solubility and significant metabolic clearance. (62, 63)
A metabolite identification and glutathione trapping experiment was carried out on OSM-S-35 in the presence of metabolic activation (human microsomes, Data Set S25). A number of metabolites were detected, mainly oxygenated species (mono-, bis-, and trioxygenated metabolites) with the predominant metabolite (based on peak area and assuming similar response factors for each metabolite) arising from likely hydroxylation of the pyrrole substituted benzene. In the presence of glutathione ethyl ester (GSH-EE), weak signals for adducts were observed for both parent compound and mono- and bisoxygenated metabolites. In the case of the parent compound, the GSH-EE adduct was observed both in the presence and in the absence of metabolic activation. Further characterization of the adducts was precluded by the very weak MS/MS spectra; however, the detection of adducts suggests that the formation of reactive species cannot be ruled out.

hERG Liability

There is increasing awareness of the importance for drug candidates of inhibition of hERG (the human ether-à-go-go-related gene ion channel), which is sensitive to blockade by many drug-like structures. Such blockage has led to a number of prominent postmarketing withdrawals. (103) Regulators are sensitive to any hERG activity, and a hERG counterscreen is often now run early in hit characterization and series prioritization. Compounds OSM-S-5 and OSM-S-35 were shown not to suffer from significant hERG activity (IC50 > 33 μM vs 0.7 μM for control compound quinidine), implying that the original ester and NN class of compounds are not likely to exhibit undesirable cardiac side effects later in development (Data Set S26, Text S11).

Late Stage Gametocyte Assay

There are relatively few compounds effective against the gametocyte stage of the parasite, (12, 13) though such compounds are important in the prevention of disease transmission. Four compounds found to be active in the asexual assay were evaluated against late stage (IV–V) gametocytes. The results (Table 1, Data Sets S27 and S28) indicated that the NN compounds OSM-S-38 and OSM-S-39 exhibited highly promising IC50 values of 4 nM and 2.6 nM respectively, comparable to the activities of artemisinin and artesunate. Compound OSM-S-9 also showed good activity while one of the original hit compounds (OSM-S-5) exhibited low levels of activity. Several compounds evaluated were found to lead to an unusual parasite morphology that may be indicative of a slow-acting mechanism of action (Supporting Information, late stage gametocyte assays 1 and 2).
Table 1. Potency vs Late Stage Gametocytes for Selected Compounds
OSM-S-late stage GAMa (nM)
575% at 60 μM
928
384
392.6
111b686
b

Value for this compound taken from Data Set S28. Controls: see the Supporting Information.

When the compounds were evaluated in a dual gamete formation assay (DGFA) (104) to evaluate separately the susceptibilities of male and female mature stage V gametocytes to both the hit ester (OSM-S-5) and a selection of NN compounds, it was found that all compounds possessed low activity at 1 μM against both sexes (Text S10). The discrepancy in the data arising from these two gametocyte assays may arise from the slightly different cell biology assayed (stage IV/V gametocytes vs stage V mature gametocytes) or most likely is a function of the relative compound exposure times (96 h vs 24 h).

Liver Stage

Liver stage activity is strategically important in antimalarial drug discovery because compounds that block development of exoerythrocytic parasite stages in hepatic cells often prove to have causal prophylactic activity in animal models. (14, 105) Three compounds (original hit OSM-S-5 and the NN compounds OSM-S-38 and -111) were assessed for their activity against sporozoites in liver cells (vs atovaquone as positive control) and displayed varying potencies (Table 2; Data Sets S29–31; Figure S31) that track with blood stage potency. Of particular note is the striking potency of the nontoxic compound OSM-S-38, which may at this level provide protection from malaria to people who have been treated with the compound after an infectious bite. Given the similarity observed in the possible mode of action (see next section), it is unclear why the arylpyrrole compound OSM-S-5 should exhibit such low levels of activity in the present assay vs the NN compounds. Possible explanations include differential solubility or stability; the level of cytotoxicity observed for OSM-S-5 suggests that the liver stage potency is probably just a generic toxic effect.
Table 2. Liver and Blood Stage Potencies for Selected Compounds
OSM-S-P. berghei IC50 (nM)cytotoxicity (HepG2, IC50, nM)blood stage potency (3D7, nM)
5a,b24000, 140009800, 18000502c
38a,b19, 13>5000079d
111e3504400147d
c

See Table SB1.

d

See Table SB3.

e

Data Set S29; Figure S31, liver stage potency curve.

Mode of Action

As with most phenotypic hit to lead projects, the activity assays were carried out on whole parasites, giving a more realistic measure of activity than enzyme-based assays at the expense of an unknown mode of action. To predict the mode of action of the members of these series, eight representative active compounds (structures in the Supporting Information) across both subseries were evaluated in a yeast-based genetic sensitivity Hip Hop assay (106, 107) that seeks mutations that result in enhanced compound potency, i.e., to identify any sensitive biological processes. The most potent compounds (OSM-S-39 and -51) showed enrichments for processes involved in chromatin remodeling and DNA repair. Indeed, inspection of the rank ordered genes for all compounds showed a preponderance of genes for diverse components of chromatin architecture, remodeling, and post-translational modification of chromatin proteins. These results are consistent with a perturbation of chromatin condensation with predicted follow-on effects on gene expression. Several groups have highlighted apparent plasticity of global gene expression in the malaria parasite which is manifested as a complex program of histone modification. (108, 109) To attempt to gain additional insight into genome wide screens, we compared the data from several OSM compounds to a data set of 3200 similar genome wide screens to identify the 10 most similar profiles for each of these OSM analogues. This provided clear concordance between these results and screens for other compounds, for OSM-S-39 (danthron, an anthraquinone derivative, as well as artemisinin), OSM-S-51 (the antineoplastics mitoxanthrone and mitomycin C), and OSM-S-9 (the antiarrhythmic agent DTBHQ). Taken together, these data point to a global dysregulation of chromatin architecture and suggest that further bioinformatics analysis both within the hip-hop data set and to orthologous data sets may be informative. The finding that the profile of the compounds is similar to that of known antimalarials (e.g., artemisinin) is provocative and warrants consideration. While it is formally possible that the predicted mechanism of select OSM compounds is similar to that of artemisinin, in our experience the degree of concordance we see between the OSM compounds and artemisinin suggests that the OSM compounds perturb a similar, but distinct, cellular target or pathway. This observation is consistent with our recent observation that, in a compendium of 3200 chemogenomic screens, the majority of compounds fell into ∼45 cellular response classes. (106) Our finding that different compounds from the same series have different profiles is also compelling and is consistent with previously published work demonstrating that single atom changes within a compound class can produce distinct cellular responses, which we attribute to small differences in compound structure resulting in significant fitness differences. (110) In order to derive experimental evidence for possible differences in mode of action, a parasite reduction ratio (PRR, generically “rate of killing”) (111) assay was run for six of these compounds (across both arylpyrrole and NN series) even though this assay is not a direct measure of differences in gene expression. The results (Text S1, Figure S37) suggest a common mechanism of action between the subseries and one that is distinct from artemisinin, which has previously exhibited a substantially faster killing profile. It remains a possibility that the in vivo target and/or impact on gene expression of the compounds in the arylpyrrole/near neighbor series are distinct and yet they still share a common mode of action, but this was not investigated further here.
The potency of the near neighbor set led to an in silico target prediction study being performed on OSM-S-39 (Text S11). The method employed a naive Bayes statistical model identifying molecular structural features of small molecules with protein targets, using the ChEMBL database. Similar statistical approaches based on known activities of compounds have been successfully applied to identify targets of antitubercular compounds. (112-114) A total of 1,287 proteins were included for which at least 50 active compounds were known with activities <10 μM, with the other compounds in the database comprising the inactives. After the OSM compounds were scored against each target, the scores obtained were standardized by comparison with scores obtained through comparison with a random set of >10K compounds. The prediction list was culled for proteins relevant to malaria (3D7 proteome), and the analysis gave as the most likely candidate targets, in order of significance, carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 (Q8I3U9), dihydroorotate dehydrogenase (DHODH, Q08210), SUMO-activating enzyme subunit 2 (Q8I553) and 1 (Q8IHS2), and cyclin-dependent kinase 1 (P61075). To kick-start the process of exploring these predictions, this compound and 24 others representative of both the hit compounds were evaluated in an experimental assay for DHODH inhibition (Data Set S36; Text S14) vs two positive control compounds (TCMDC-125840 and -123822) known to inhibit this enzyme. (115) None of the compounds exhibited any activity, strongly suggesting that this is not the target for either subseries of compounds. A line of inquiry remaining open is the equivalent assays against the other targets identified in the in silico prediction.
Involvement of PfATP4, a putative plasma membrane ion pump, in the mechanism of action was ruled out. The relevant experiments measure the effect of a compound on the cytosolic [Na+] ([Na+]i) in isolated (trophozoite-stage) parasites preloaded with the Na+-sensitive fluorescent indicator SBFI. PfATP4 is important since it is the proposed target of the antimalarial compound KAE609 (116) that has recently successfully completed phase 2 trials, (117) as well as that of a pyrazoleamide (118) a dihydroisoquinolone ((+)-SJ-733), (119) various aminopyrazoles, (120) 28 of the 400 potent antiplasmodial compounds comprising the MMV Malaria Box, (121) and a triazolopyrazine series being investigated by the Open Source Malaria Consortium. (122) All of these compounds cause an immediate increase in parasite [Na+]i on addition to isolated parasites. Here, several compounds across both subseries were tested at 1 μM for their effect on [Na+]i in saponin-isolated SBFI-loaded trophozoite stage 3D7 parasites. (116) In each case there was no significant effect on [Na+]i, consistent with PfATP4 not being the relevant biological target of this compound class (Data Set S37; Figure S38).

Conclusions

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The public deposition of novel antimalarial hits from phenotypic whole-cell assays has had a significant effect on worldwide antimalarial drug discovery by providing an embarrassment of riches for the early stages of discovery. The plethora of alternative structures available for investigation has ultimately led to the series described in this paper being “parked” in favor of other possible avenues of inquiry. Interestingly the “stop” decision was straightforward to make in part because the decisions taken communally in the project had to be justifiable to all onlookers. The time taken to reach the stop decision in this case was probably slightly longer than would be expected from a traditionally structured project because certain contributions were not paid for or grant-supported, necessitating a lower priority than core interests of the contributing laboratories.
Both subseries investigated have members with major strengths, including potency with low molecular weight and significant late stage gametocyte and liver-stage activity coupled with low toxicity and low levels of activity in the hERG assay. Indeed, OSM-S-5 is bioavailable. Many of the most obvious structural changes to the hits, in several cases changes of a single atom, led to total loss, rather than moderation, of biological activity, known colloquially as “activity cliffs” (Figure 7). In the case of the ester-containing hit OSM-S-5, the ester was likely the key metabolic liability but could not be replaced with other common isosteres without loss of activity, yet (in the mouse model, at least) was found to be too short-lived in plasma to be taken on further. Other minor changes remote from the ester were also found to result in a precipitous decrease in potency. The “near neighbor” analogue set displayed impressive potency coupled with low cytotoxicity but alongside low solubility that could not easily be engineered out through side chain modifications.

Figure 7

Figure 7. Sensitivity of the initial hit OSM-S-5 to minor structural changes.

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The emergence of large amounts of open data in the field of drug discovery for malaria makes it straightforward to search for new ways forward in a project where a stop decision has been made. A similarity network map was generated for the most potent compound identified (OSM-S-39, Data Set S38, Figure S39) that identifies those compounds most similar in structure known to the open databases (Figure 8). Some of these are now represented in the MMV Malaria Box, (123) making simpler their investigation by other groups. A portion of this map is represented, alongside the structures and potencies of the closest neighbors in the map. While it is clear from this analysis that OSM-S-39 remains the most potent compound identified in this class, exploration of the neighboring structures in such open data sets may identify a way forward for this series that could suggest unexplored strategies to increase solubility with a realistic chance of maintaining potency, such as the potential scaffold-hop to the triazine TCMDC-125770. (One of the compounds shown from the Novartis screen, GNF-Pf-5137/1137, is from the same series as the published pyrrolones. (62)) The recommended way forward, rather than further analogue synthesis in the present series, is to pursue clarity in the mechanisms of action of such series using, for example, generation of resistance coupled with genomic sequencing, or pull-down studies. Subsequent screening might then establish better starting points from related structures (informed by what has already been tried via comparison with network maps) against the relevant target.

Figure 8

Figure 8. Closest neighbors of OSM-S-39. (Left) Portion of a network similarity map generated for OSM-S-39 (coded as batch ZYH-72 in the figure) using methods described in the Supporting Information. (Right) The structures (stereochemistry assumed) and potencies (3D7, range if multiple values reported) of the most similar compounds in the ChEMBL database (v13) (key to compound sources: red = GSK TCAMS, blue = Novartis, green = St. Jude’s).

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One of the unique features of this project, the open source research method, ensures that the unexplored lines of inquiry remain open alongside the attendant data posted online that makes it straightforward for others to resume any portion of the research project as fully fledged participants, with access to both positive and negative data, details of all procedures as they were carried out (to aid reproducibility), and anecdotal insight into project loose ends that are easy to explore. The machine-readability of the present project (for example the use of cheminformatic strings in the online electronic lab notebook) permits an unusually straightforward link between a high throughput screening result in a public database and a “live” research project that has investigated that compound.
Contributions to this project arose from disparate sources: (i) core government/NGO/foundation support, via both direct grant support and in-kind contributions (it is likely that direct support from public/philanthropic funds will always be needed as part of any open source drug discovery campaign); (ii) additional compound synthesis by undergraduate or postgraduate university students, either individually or as part of crowdsourced classes; (iii) expertise and advice emerging from the wider online community, both solicited and spontaneous; and (iv) additional laboratory contributions from other specialist centers, such as academic laboratories with block grants or pharmaceutical companies. These sources have considerable potential and can be mobilized further. For example, the time of researchers in major organizations (pharmaceutical companies, universities, CROs) could be contributed via policies that allow staff to work part-time on their own projects mimicking the pro bono system of the major law firms; such policies have been sporadically adopted (Figure S40) (124) and are a component of the GSK Tres Cantos research campus that kick-started and then supported the work described in this paper. In cases where resources are not forthcoming, direct payment (e.g., generated through crowdsourcing) could be awarded via competition, as occurred in this paper to create the graphical abstract. Each situation in the diverse base of support for an open source project will be different, and may be driven by appropriate selfless and selfish motives (e.g., contribution to a public health project vs securing publication authorship). Besides the transparency and completeness of the data arising from the research, this experiment with open source drug discovery made clear some of the advantages of this way of working: the breadth of people and expertise arising from “external” sources that were contributed rather than actively solicited, such as successful compound synthesis by federated groups of graduate and undergraduate students, or the analysis of data obtained by others. Allowing participation by “strangers” introduces costs, such as the time required by a “core” team to maintain the project status, data, and methodology to allow meaningful contributions (in particular a real-time data set making clear the series SAR). We predict that tools and practices will arise to make easier some of these challenges, as open source methods in drug discovery and development become more widely adopted.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.6b00086.

  • Complete electronic laboratory notebooks, images of NMR spectra for novel compounds, and archived snapshots of OSM wiki pages are available from The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/14132, http://hdl.handle.net/2123/14123, and http://hdl.handle.net/2123/15389, respectively.

  • Chemical and biological protocols, other text-based files, and screengrabs (PDF)

  • All molecules (XLS)

  • All molecules in SDF format (ZIP)

  • Potency data from Ralph assay 1 (XLS)

  • Potency data from GSK assay 1 (XLS)

  • Potency data from Avery assay 1 (XLS)

  • Similarity network data for Tres Cantos series in Cytoscape format (ZIP)

  • Map of purchaseable compounds around OSM-S-35 in Cytoscape format (ZIP)

  • Potency data from Ralph assay 2 (ZIP)

  • Potency data from GSK assay 2 (XLS)

  • Potency data from Avery assay 2 (XLS)

  • Potency data from Avery assay 3a (PDF)

  • Potency data from Avery assay 3b (XLS)

  • X-ray structural information for OSM-S-35, -42, -54, and -9 (ZIP)

  • Potency data from Avery assay 5 (XLS)

  • Potency data from Guy assay (XLS)

  • Potency data from Avery assay 3c (XLS)

  • Potency data from Dundee assay 1 (PDF)

  • Potency data from Dundee assay 2 (PDF)

  • Bioisostere analysis in Cytoscape format (ZIP)

  • Solubility and microsomal stability data for OSM-S-5, -6, -9, -10, -37, -38, -39, and -54 (ZIP)

  • Solubility and microsomal stability data for OSM-S-111 (XLS)

  • Data from oral in vivoP. berghei mouse trial for compounds OSM-S-5, -6, and -35 (XLS)

  • Pharmacokinetic data from oral in vivoP. berghei mouse trial (XLS)

  • Human and mouse plasma stability data for OSM-S-5 (XLS)

  • Metabolite identification assay data for OSM-S-35 in human liver microsomes (XLS)

  • hERG assay data for compounds OSM-S-5 and -35 (XLS)

  • Avery late stage gametocyte assay 1 (XLS)

  • Avery late stage gametocyte assay 2 (XLS)

  • UCSD liver stage assay 1 (XLS)

  • UCSD liver stage assay 2 (XLS)

  • UCSD liver stage assay 3 (XLS)

  • Nislow gene set enrichment analysis data (XLS)

  • Nislow gene set enrichment analysis data, Spotfire format (ZIP)

  • Nislow gene set enrichment analysis data (PDF)

  • Nislow fitness defect scores for all deletion strains (XLS)

  • Data from GSK DHODH assay (XLS)

  • Data from Kirk ion regulation assay (XLS)

  • Similarity map surrounding OSM-S-39 in Cytoscape format (ZIP)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Authors
    • Alice E. Williamson - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Paul M. Ylioja - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Murray N. Robertson - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Yevgeniya Antonova-Koch - Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
    • Vicky Avery - Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
    • Jonathan B. Baell - Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
    • Harikrishna Batchu - CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
    • Sanjay Batra - CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
    • Jeremy N. Burrows - Medicines for Malaria Venture, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland
    • Soumya Bhattacharyya - CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
    • Felix Calderon - Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
    • Susan A. Charman - Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
    • Julie Clark - Department of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States
    • Benigno Crespo - Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
    • Matin Dean - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Stefan L. Debbert - Department of Chemistry, Lawrence University, 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911, United States
    • Michael Delves - Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, U.K.
    • Adelaide S. M. Dennis - Research School of Biology, The Australian National University, Canberra, ACT 2601, Australia
    • Frederik Deroose - Asclepia Outsourcing Solutions, Damvalleistraat 49, B-9070 Destelbergen, Belgium
    • Sandra Duffy - Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
    • Sabine Fletcher - Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
    • Guri Giaever - Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
    • Irene Hallyburton - Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, U.K.
    • Francisco-Javier Gamo - Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
    • Marinella Gebbia - Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
    • R. Kiplin Guy - Department of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States
    • Zoe Hungerford - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Kiaran Kirk - Research School of Biology, The Australian National University, Canberra, ACT 2601, Australia
    • Maria J. Lafuente-Monasterio - Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
    • Anna Lee - Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
    • Stephan Meister - Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
    • Corey Nislow - Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
    • John P. Overington - European Molecular Biology Laboratory—European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
    • George Papadatos - European Molecular Biology Laboratory—European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
    • Luc Patiny - Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland
    • James Pham - Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria 3010, Australia
    • Stuart A. Ralph - Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria 3010, Australia
    • Andrea Ruecker - Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, U.K.
    • Eileen Ryan - Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
    • Christopher Southan - IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, EH8 9XD, U.K.
    • Kumkum Srivastava - CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
    • Chris Swain - Cambridge MedChem Consulting, 8 Mangers Lane, Duxford, Cambridge CB22 4RN, U.K.
    • Matthew J. Tarnowski - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Patrick Thomson - School of Chemistry, The University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
    • Peter Turner - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Iain M. Wallace - European Molecular Biology Laboratory—European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
    • Timothy N. C. Wells - Medicines for Malaria Venture, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland
    • Karen White - Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
    • Laura White - School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
    • Paul Willis - Medicines for Malaria Venture, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland
    • Elizabeth A. Winzeler - Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
    • Sergio Wittlin - Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland
  • Funding

    Medicines for Malaria Venture (MMV), the Australian Research Council (LP120100552, LP120200557), the Australian National Health and Medical Research Council (Project Grant 1042272). G.P. and J.P.O. were supported by EMBL Member States and MMV. The characterization by NMR spectroscopy of compounds from Lawrence University was made possible by the National Science Foundation (CHE-0923473). C.S. was supported by Wellcome Trust Biomedical Resources Grant 099156/Z/12/Z.

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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We would like to thank the Labtrove team at the University of Southampton led by Professor Jeremy Frey, OpenWetWare for hosting the OSM wiki, and publicly available platforms such as Twitter, G+, Facebook, and Github that have helped in the wider dissemination required for live research projects. We thank Michael Robins for ongoing technical support of the online project components. OSM-A-1 through -A-4 were synthesized by undergraduate organic chemistry students at Lawrence University; in particular, the work of Shay Albrecht, Margaret Brickner, Patrick Doughty, Joshua Graber, Sarah Gunby, Briana Harter, Alexander Hurlburt, Jake Johengen, Sarah Prophet, Greta Schmitt, Chad Skaer, and Konstantinos Vlachos is acknowledged. Dr. Colin Campbell (The University of Edinburgh) is thanked for provision of laboratory resources and time, as is the University of Edinburgh for funding (to P.T.). The Australian Red Cross Blood Service is thanked for the provision of blood (to K.K. and V.A.). The authors wish to thank Prof. David Fidock (Columbia University, NY) for the provision of the NF54 transgenic parasite expressing GFP linked to the early expressed gametocyte specific protein, Pfs16. Miscellaneous project inputs were gratefully received from William Jackson (Creative Chemistry), Egon Willighagen (Maastricht University), Martine Keenan (Epichem), Darren Dressen (Los Altos High School), Robert Snell (The University of Cambridge, now Charterhouse School) and Joie Garfunkel (Merck). For their generous time and insights, we thank the other (sometimes anonymous) online contributors. We thank Viputheshwar Sitaraman (Draw Science) for creating the graphical abstract as part of a competition for this purpose. We thank Ginger Taylor for creating The Synaptic Leap website, which hosted much of the early activity in the project. We would like to thank student volunteers (Min Kyung Chong, Jun Ki Hong, Martina Yousif, Sebastien Dath) for help with online data entry.

References

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    Artemisinin resistance in Plasmodium falciparum malaria
    Dondorp, Arjen M.; Nosten, Francois; Yi, Poravuth; Das, Debashish; Phyo, Aung Phae; Tarning, Joel; Lwin, Khin Maung; Ariey, Frederic; Hanpithakpong, Warunee; Lee, Sue J.; Ringwald, Pascal; Silamut, Kamolrat; Imwong, Mallika; Chotivanich, Kesinee; Lim, Pharath; Herdman, Trent; Sam An, Sen; Yeung, Shunmay; Singhasivanon, Pratap; Day, Nicholas P. J.; Lindegardh, Niklas; Socheat, Duong; White, Nicholas J.
    New England Journal of Medicine (2009), 361 (5), 455-467CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kg of body wt. per day, for 7 days, and artesunate given at a dose of 4 mg per kg per day, for 3 days, followed by mefloqine at two doses totaling 25 mg per kg. We assessed in vitro and in vivo Plasmodium-falciparum susceptibility, artesunate pharmacokinetics, and mol. markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 h (interquartile range, 60 to 96) in Pailin and 48 h (interquartile range, 36 to 66) in Wang Pha (P < 0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloqine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), resp., in Wang Pha (P = 0.31). These markedly different parasitol. responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative mol. correlates of P.falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P.falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding redns. on conventional in vitro susceptibility testing. Containment measures are urgently needed.
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  6. 6
    Phyo, A. P.; Nkhoma, S.; Stepniewska, K.; Ashley, E. A.; Nair, S.; McGready, R. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study Lancet 2012, 379, 1960– 1966 DOI: 10.1016/S0140-6736(12)60484-X
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    6
    Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study
    Phyo Aung Pyae; Nkhoma Standwell; Stepniewska Kasia; Ashley Elizabeth A; Nair Shalini; McGready Rose; ler Moo Carit; Al-Saai Salma; Dondorp Arjen M; Lwin Khin Maung; Singhasivanon Pratap; Day Nicholas P J; White Nicholas J; Anderson Tim J C; Nosten Francois
    Lancet (London, England) (2012), 379 (9830), 1960-6 ISSN:.
    BACKGROUND: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border. METHODS: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. FINDINGS: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. INTERPRETATION: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years. FUNDING: The Wellcome Trust and National Institutes of Health.
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  7. 7
    RTS,S Clinical Trials Partnership Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomized, controlled trial Lancet 2015, 386, 31– 45 DOI: 10.1016/S0140-6736(15)60721-8
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    Olotu, A.; Fegan, G.; Wambua, J.; Nyangweso, G.; Awuondo, K. O.; Leach, A. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure N. Engl. J. Med. 2013, 368, 1111– 1120 DOI: 10.1056/NEJMoa1207564
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    Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure
    Olotu, Ally; Fegan, Gregory; Wambua, Juliana; Nyangweso, George; Awuondo, Ken O.; Leach, Amanda; Lievens, Marc; Leboulleux, Didier; Njuguna, Patricia; Peshu, Norbert; Marsh, Kevin; Bejon, Philip
    New England Journal of Medicine (2013), 368 (12), 1111-1120CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    BACKGROUND: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited. METHODS: For 4 years, we followed children who had been randomly assigned, at 5 to 17 mo of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clin. malaria (temp. of ≥37.5°C and Plasmodium falciparum parasitemia d. of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estd. with the use of the distance-weighted local prevalence of malaria. RESULTS: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clin. malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P = 0.005) and 32.1% (95% CI, 11.6 to 47.8; P = 0.004), resp., calcd. by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, resp.; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P = 0.18) and 24.3% (95% CI, 1.9 to 41.6; P = 0.04), resp., calcd. by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clin. malaria were averted. Vaccine efficacy declined over time (P = 0.004) and with increasing exposure to malaria (P = 0.001) in the per-protocol anal. Vaccine efficacy was 43.6% (95%, CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was av. or lower than av., the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than av. it was 15.9% (95% CI, -11.0 to 36.4). CONCLUSIONS: The efficacy of RTS,S/AS01E vaccine over the 4-yr period was 16.8%. Efficacy declined over time and with increasing malaria exposure.
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    Wells, T. N. C.; van Huijsduijnen, R. H.; Van Voorhis, W. C. Malaria medicines: a glass half full? Nat. Rev. Drug Discovery 2015, 14, 424– 442 DOI: 10.1038/nrd4573
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    Malaria medicines: a glass half full?
    Wells, Timothy N. C.; Hooft van Huijsduijnen, Rob; Van Voorhis, Wesley C.
    Nature Reviews Drug Discovery (2015), 14 (6), 424-442CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compd. or product profiles, to assess progress and gaps, and to recommend priorities.
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    Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A. Antimalarial drug discovery – approaches and progress towards new medicines Nat. Rev. Microbiol. 2013, 11, 849– 862 DOI: 10.1038/nrmicro3138
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    Antimalarial drug discovery - approaches and progress towards new medicines
    Flannery, Erika L.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.
    Nature Reviews Microbiology (2013), 11 (12), 849-862CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
    A review. Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public-private partnerships are funding innovative approaches to identify compds. that target multiple parasite species at multiple stages of the parasite life cycle. In this Review, we discuss the cell-, chem.- and target-based approaches used to discover new drug candidates that are currently in clin. trials or undergoing preclin. testing.
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    Burrows, J. N.; Elliott, R. L.; Kaneko, T.; Mowbray, C. E.; Waterson, D. The role of modern drug discovery in the fight against neglected and tropical diseases MedChemComm 2014, 5, 688– 700 DOI: 10.1039/c4md00011k
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    11
    The role of modern drug discovery in the fight against neglected and tropical diseases
    Burrows, Jeremy N.; Elliott, Richard L.; Kaneko, Takushi; Mowbray, Charles E.; Waterson, David
    MedChemComm (2014), 5 (6), 688-700CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    A review. Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technol. investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chem. diverse compd. libraries to enable lead discovery remains one of the crit. bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
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    Peatey, C. L.; Leroy, D.; Gardiner, D. L.; Trenholme, K. R. Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes? Malar. J. 2012, 11, 34 DOI: 10.1186/1475-2875-11-34
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    12
    Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes?
    Peatey Christopher L; Leroy Didier; Gardiner Donald L; Trenholme Katharine R
    Malaria journal (2012), 11 (), 34 ISSN:.
    BACKGROUND: Recent renewed emphasis on the eradication of malaria has highlighted the need for more tools with which to achieve this ambitious goal. One high priority area is the need to determine the gametocytocidal activity of both currently used anti-malarial drugs and those in the development pipeline. However, testing the activity of compounds against Plasmodium falciparum gametocytes is technically challenging both in vivo and in vitro. METHODS: Here the use of a simple robust assay to screen a panel of currently used and experimental anti-malarial drugs against mature P. falciparum gametocytes is described. RESULTS: Eight of 44 compounds tested reduced gametocyte viability by at least 50% and three showed IC50 values in nM range. CONCLUSIONS: There is a need to identify new compounds with activity against late stage gametocytes and the information provided by this in vitro assay is a valuable first step, which can guide future clinical studies.
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    Duffy, S.; Avery, V. M. Identification of inhibitors of Plasmodium falciparum gametocyte development Malar. J. 2013, 12, 408 DOI: 10.1186/1475-2875-12-408
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    13
    Identification of inhibitors of Plasmodium falciparum gametocyte development
    Duffy, Sandra; Avery, Vicky M.
    Malaria Journal (2013), 12 (), 408/1-408/15, 15 pp.CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
    Background: Plasmodium falciparum gametocytes, specifically mature stages, are the only stage in man transmissible to the mosquito vector responsible for malaria transmission. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria. The comprehensive profiling of in vitro activity of anti-malarial compds. against both early (I-III) and late (IV-V) stage P. falciparum gametocytes, along with the high throughput screening (HTS) outcomes from the MMV malaria box are described. Method: Two anti-gametocyte HTS assays based on confocal fluorescence microscopy, utilizing both a gametocyte specific protein (pfs16-Luc-GFP) and a viability marker (MitoTracker Red CM-H2XRos) (MTR), were used for the measurement of anti-gametocytocidal activity. This combination provided a direct observation of gametocyte no. per assay well, while defining the viability of each gametocyte imaged. Results: IC50 values were obtained for 36 current anti-malarial compds. for activities against asexual, early and late stage gametocytes. The MMV malaria box was screened and actives progressed for IC50 evaluation. Seven % of the "drug-like" and 21% of the "probe-like" compds. from the MMV malaria box demonstrated equiv. activity against both asexual and late stage gametocytes. Conclusions: The assays described were shown to selectively identify compds. with gametocytocidal activity and have been demonstrated suitable for HTS with the capability of screening in the order of 20,000 compds. per screening campaign, two to three times per seven-day week.
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    McNamara, C. W.; Lee, M. C. S.; Lim, C. S.; Lim, S. H.; Roland, J.; Nagle, A. Targeting Plasmodium PI(4)K to eliminate malaria Nature 2013, 504, 248– 253 DOI: 10.1038/nature12782
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    Targeting Plasmodium PI(4)K to eliminate malaria
    McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.
    Nature (London, United Kingdom) (2013), 504 (7479), 248-253CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here the authors identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compd. class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. The authors show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, the authors' data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
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    Dembélé, L.; Franetich, J.-F.; Lorthiois, A.; Gego, A.; Zeeman, A.-M.; Kocken, C. H. M. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures Nat. Med. 2014, 20, 307– 312 DOI: 10.1038/nm.3461
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    Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures
    Dembele, Laurent; Franetich, Jean-Francois; Lorthiois, Audrey; Gego, Audrey; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Le Grand, Roger; Dereuddre-Bosquet, Nathalie; van Gemert, Geert-Jan; Sauerwein, Robert; Vaillant, Jean-Christophe; Hannoun, Laurent; Fuchter, Matthew J.; Diagana, Thierry T.; Malmquist, Nicholas A.; Scherf, Artur; Snounou, Georges; Mazier, Dominique
    Nature Medicine (New York, NY, United States) (2014), 20 (3), 307-312CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compds. that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, exptl. infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept expt., we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biol. and the search for compds. that kill hypnozoites or disrupt their quiescence.
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    Scannell, J. W.; Blanckley, A.; Boldon, H.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency Nat. Rev. Drug Discovery 2012, 11, 191– 200 DOI: 10.1038/nrd3681
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    Diagnosing the decline in pharmaceutical R&D efficiency
    Scannell, Jack W.; Blanckley, Alex; Boldon, Helen; Warrington, Brian
    Nature Reviews Drug Discovery (2012), 11 (3), 191-200CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. The past 60 years have seen huge advances in many of the scientific, technol. and managerial factors that should tend to raise the efficiency of com. drug research and development (RD). Yet the no. of new drugs approved per billion US dollars spent on RD has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solns. to the problem of declining RD efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the no. of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research-brute force' bias. Our aim is to provoke a more systematic anal. of the causes of the decline in RD efficiency.
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    Paul, S. M.; Mytelka, D. S.; Dunwiddie, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R. How to improve R&D productivity: the pharmaceutical industry’s grand challenge Nat. Rev. Drug Discovery 2010, 9, 203– 214 DOI: 10.1038/nrd3078
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    How to improve R&D productivity: the pharmaceutical industry's grand challenge
    Paul, Steven M.; Mytelka, Daniel S.; Dunwiddie, Christopher T.; Persinger, Charles C.; Munos, Bernard H.; Lindborg, Stacy R.; Schacht, Aaron L.
    Nature Reviews Drug Discovery (2010), 9 (3), 203-214CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the no. and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a no. of years. Here, we present a detailed anal. based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.
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    Kneller, R. The importance of new companies for drug discovery: origins of a decade of new drugs Nat. Rev. Drug Discovery 2010, 9, 867– 882 DOI: 10.1038/nrd3251
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    Lotharius, J.; Gamo-Benito, F. J.; Angulo-Barturen, I.; Clark, J.; Connelly, M.; Ferrer-Bazaga, S. Repositioning: the fast track to new anti-malarial medicines? Malar. J. 2014, 13, 143 DOI: 10.1186/1475-2875-13-143
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    Repositioning: the fast track to new anti-malarial medicines?
    Lotharius Julie; Gamo-Benito Francisco Javier; Angulo-Barturen Inigo; Clark Julie; Connelly Michele; Ferrer-Bazaga Santiago; Parkinson Tanya; Viswanath Pavithra; Bandodkar Balachandra; Rautela Nikhil; Bharath Sowmya; Duffy Sandra; Avery Vicky M; Guy R Kiplin; Wells Timothy; Mohrle Jorg J
    Malaria journal (2014), 13 (), 143 ISSN:.
    BACKGROUND: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. METHODS: Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [(3)H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model. RESULTS: Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model. CONCLUSIONS: Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at μM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
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    Can open-source drug R&D repower pharmaceutical innovation?
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    Open-source R&D initiatives are multiplying across biomedical research. Some of them-such as public-private partnerships-have achieved notable success in bringing new drugs to market economically, whereas others reflect the pharmaceutical industry's efforts to retool its R&D model. Is open innovation the answer to the innovation crisis? This Commentary argues that although it may likely be part of the solution, significant cultural, scientific, and regulatory barriers can prevent it from delivering on its promise.
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    Open science is a research accelerator
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    Nature Chemistry (2011), 3 (10), 745-748CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    A review with commentary. An open-source approach to the problem of producing an off-patent drug in enantiopure form serves as an example of how academic and industrial researchers can join forces to make new scientific discoveries that could have a huge impact on human health.
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    Ortí, L.; Carbajo, R. J.; Pieper, U.; Eswar, N.; Maurer, S. M.; Rai, A. K. A kernel for open source drug discovery in tropical diseases PLoS Neglected Trop. Dis. 2009, 3, e418 DOI: 10.1371/journal.pntd.0000418
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    Årdal, C.; Alstadsæter, A.; Røttingen, J. A. Common characteristics of open source software development and applicability for drug discovery: a systematic review Health Res. Policy Syst. 2011, 9, 36 DOI: 10.1186/1478-4505-9-36
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    Common characteristics of open source software development and applicability for drug discovery: a systematic review
    Ardal Christine; Alstadsaeter Annette; Rottingen John-Arne
    Health research policy and systems / BioMed Central (2011), 9 (), 36 ISSN:.
    BACKGROUND: Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. METHODS: A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. RESULTS: Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. CONCLUSIONS: We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.
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    The case for open-source software in drug discovery
    DeLano, Warren L.
    Drug Discovery Today (2005), 10 (3), 213-217CODEN: DDTOFS; ISSN:1359-6446. (Elsevier)
    A review. Widespread adoption of open-source software for network infrastructure, web servers, code development, and operating systems leads one to ask how far it can go. Will open source' spread broadly, or will it be restricted to niches frequented by hopeful hobbyists and midnight hackers Here we identify reasons for the success of open-source software and predict how consumers in drug discovery will benefit from new open-source products that address their needs with increased flexibility and in ways complementary to proprietary options.
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    Woelfle, M.; Seerden, J.-P.; de Gooijer, J.; Pouwer, K.; Olliaro, P.; Todd, M. H. Resolution of praziquantel PLoS Neglected Trop. Dis. 2011, 5, e1260 DOI: 10.1371/journal.pntd.0001260
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    Resolution of praziquantel
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    PLoS Neglected Tropical Diseases (2011), 5 (9), e1260CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
    Background: Praziquantel remains the drug of choice for the worldwide treatment and control of schistosomiasis. The drug is synthesized and administered as a racemate. Use of the pure active enantiomer would be desirable since the inactive enantiomer is assocd. with side effects and is responsible for the extremely bitter taste of the pill. Methodol./Principal Findings: We have identified two resoln. approaches toward the prodn. of praziquantel as a single enantiomer. One approach starts with com. available praziquantel and involves a hydrolysis to an intermediate amine, which is resolved with a deriv. of tartaric acid. This method was discovered through an open collaboration on the internet. The second method, identified by a contract research organization, employs a different intermediate that may be resolved with tartaric acid itself. Conclusions/Significance: Both resoln. procedures identified show promise for the large-scale, economically viable prodn. of praziquantel as a single enantiomer for a low price. Addnl., they may be employed by labs. for the prodn. of smaller amts. of enantiopure drug for research purposes that should be useful in, for example, elucidation of the drug's mechanism of action.
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    Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells
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    Science (Washington, DC, United States) (2012), 337 (6093), 470-473CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    A strain of Halomonas bacteria, GFAJ-1, has been claimed to be able to use arsenate as a nutrient when phosphate is limiting and to specifically incorporate arsenic into its DNA in place of phosphorus. However, the authors have found that arsenate does not contribute to growth of GFAJ-1 when phosphate is limiting and that DNA purified from cells grown with limiting phosphate and abundant arsenate does not exhibit the spontaneous hydrolysis expected of arsenate ester bonds. Furthermore, mass spectrometry showed that this DNA contains only trace amts. of free arsenate and no detectable covalently bound arsenate.
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    New England Journal of Medicine (2013), 368 (9), 789-791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
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    Robertson, M. N.; Ylioja, P. M.; Williamson, A. E.; Woelfle, M.; Robins, M.; Badiola, K. A. Open source drug discovery - a limited tutorial Parasitology 2014, 141, 148– 157 DOI: 10.1017/S0031182013001121
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    Badiola, K. A.; Bird, C.; Brocklesby, W. S.; Casson, J.; Chapman, R. T.; Coles, S. J. Experiences with a researcher-centric ELN Chem. Sci. 2015, 6, 1614– 1629 DOI: 10.1039/C4SC02128B
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    Experiences with a researcher-centric ELN
    Badiola, Katrina A.; Bird, Colin; Brocklesby, William S.; Casson, John; Chapman, Richard T.; Coles, Simon J.; Cronshaw, James R.; Fisher, Adam; Frey, Jeremy G.; Gloria, Danmar; Grossel, Martin C.; Hibbert, D. Brynn; Knight, Nicola; Mapp, Lucy K.; Marazzi, Luke; Matthews, Brian; Milsted, Andy; Minns, Russell S.; Mueller, Karl T.; Murphy, Kelly; Parkinson, Tim; Quinnell, Rosanne; Robinson, John S.; Robertson, Murray N.; Robins, Michael; Springate, Emma; Tizzard, Graham; Todd, Matthew H.; Williamson, Alice E.; Willoughby, Cerys; Yang, Erica; Ylioja, Paul M.
    Chemical Science (2015), 6 (3), 1614-1629CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A review. Electronic Lab. Notebooks (ELNs) are progressively replacing traditional paper books in both com. research establishments and academic institutions. University researchers require specific features from ELNs, given the need to promote cross-institutional collaborative working, to enable the sharing of procedures and results, and to facilitate publication. The LabTrove ELN, which we use as our exemplar, was designed to be researcher-centric (i.e., not only aimed at the individual researcher's basic needs rather than to a specific institutional or subject or disciplinary agenda, but also able to be tailored because it is open source). LabTrove is being used in a heterogeneous set of academic labs., for a range of purposes, including anal. chem., X-ray studies, drug discovery and a biomaterials project. Researchers use the ELN for recording expts., preserving data collected, and for project coordination. This perspective article describes the experiences of those researchers from several viewpoints, demonstrating how a web-based open source electronic notebook can meet the diverse needs of academic researchers.
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    Gamo, F.-J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.-L. Thousands of chemical starting points for antimalarial lead identification Nature 2010, 465, 305– 310 DOI: 10.1038/nature09107
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    Thousands of chemical starting points for antimalarial lead identification
    Gamo, Francisco-Javier; Sanz, Laura M.; Vidal, Jaume; de Cozar, Cristina; Alvarez, Emilio; Lavandera, Jose-Luis; Vanderwall, Dana E.; Green, Darren V. S.; Kumar, Vinod; Hasan, Samiul; Brown, James R.; Peishoff, Catherine E.; Cardon, Lon R.; Garcia-Bustos, Jose F.
    Nature (London, United Kingdom) (2010), 465 (7296), 305-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chem. class of antimalarials has been introduced into clin. practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compds. in GlaxoSmithKline's chem. library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 μM concn. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compds. originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chem. structures and assocd. data are hereby made public to encourage addnl. drug lead identification efforts and further research into this disease.
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    Guiguemde, W. A.; Shelat, A. A.; Bouck, D.; Duffy, S.; Crowther, G. J.; Davis, P. H. Chemical genetics of Plasmodium falciparum Nature 2010, 465, 311– 315 DOI: 10.1038/nature09099
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    Chemical genetics of Plasmodium falciparum
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    Nature (London, United Kingdom) (2010), 465 (7296), 311-315CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per yr worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chem. genetic approach to assay 309,474 chems. Here we disclose structures and biol. activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chem. genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compd. displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
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    Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 9059– 9064 DOI: 10.1073/pnas.0802982105
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    In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen
    Plouffe, David; Brinker, Achim; McNamara, Case; Henson, Kerstin; Kato, Nobutaka; Kuhen, Kelli; Nagle, Advait; Adrian, Francisco; Matzen, Jason T.; Anderson, Paul; Nam, Tae-gyu; Gray, Nathanael S.; Chatterjee, Arnab; Janes, Jeff; Yan, S. Frank; Trager, Richard; Caldwell, Jeremy S.; Schultz, Peter G.; Zhou, Yingyao; Winzeler, Elizabeth A.
    Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (26), 9059-9064CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈ 1.7 million compds., we identified a diverse collection of ≈ 6,000 small mols. comprised of > 530 distinct scaffolds, all of which show potent antimalarial activity (< 1.25 μM). Most known antimalarials were identified in this screen, thus validating our approach. In addn., we identified many novel chem. scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be detd. by in silico compd. activity profiling. This method uses large datasets from unrelated cellular and biochem. screens and the guilt-by-assocn. principle to predict which cellular pathway and/or protein target is being inhibited by select compds. In addn., the screening method has the potential to provide the malaria community with many new starting points for the development of biol. probes and drugs with novel antiparasitic activities.
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    Calderón, F.; Barros, D.; Bueno, J. M.; Coterón, J. M.; Fernández, E.; Gamo, F. J. An invitation to open innovation in malaria drug discovery: 47 quality starting points from the TCAMS ACS Med. Chem. Lett. 2011, 2, 741– 746 DOI: 10.1021/ml200135p
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    An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS
    Calderon, Felix; Barros, David; Bueno, Jose Maria; Coteron, Jose Miguel; Fernandez, Esther; Gamo, Francisco Javier; Lavandera, Jose Luis; Leon, Maria Luisa; MacDonald, Simon J. F.; Mallo, Araceli; Manzano, Pilar; Porras, Esther; Fiandor, Jose Maria; Castro, Julia
    ACS Medicinal Chemistry Letters (2011), 2 (10), 741-746CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    In 2010, GlaxoSmithKline published the structures of 13533 chem. starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochem. properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clin. candidates.
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    Rueda, L.; Castellote, I.; Castro-Pichel, J.; Chaparro, M. J.; de la Rosa, J. C.; Garcia-Perez, A. Cyclopropyl carboxamides: a new oral antimalarial series derived from the Tres Cantos anti-malarial set (TCAMS) ACS Med. Chem. Lett. 2011, 2, 840– 844 DOI: 10.1021/ml2001517
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    Murugesan, Dinakaran; Mital, Alka; Kaiser, Marcel; Shackleford, David M.; Morizzi, Julia; Katneni, Kasiram; Campbell, Michael; Hudson, Alan; Charman, Susan A.; Yeates, Clive; Gilbert, Ian H.
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    In the pursuit of new antimalarial leads, a phenotypic screening of various com. sourced compd. libraries was undertaken by the World Health Organization Program for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (I), which showed potent activity against Plasmodium falciparum K1 (EC50 ∼ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered i.p. Structure-activity relationship studies have indicated ways in which the mol. could be optimized. This compd. represents an exciting start point for a drug discovery program for the development of a novel antimalarial.
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    Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum
    Avery, Vicky M.; Bashyam, Sridevi; Burrows, Jeremy N.; Duffy, Sandra; Papadatos, George; Puthukkuti, Shyni; Sambandan, Yuvaraj; Singh, Shivendra; Spangenberg, Thomas; Waterson, David; Willis, Paul
    Malaria Journal (2014), 13 (), 190/1-190/26, 26CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
    Background In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e g, new modes of action, transmission-blocking activity or long-duration chemo-protection), a chem. library consisting of more than 250,000 compds. has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chem. diversity and novelty. Methods The selection cascade used for the triaging of hits from the chem. library started with a robust three-step in vitro assay followed by an in silico anal. of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational anal. to assess chem. properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chem. space defined by the hits. Then, in cerebro evaluation of the chem. structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chem. programs. Next, prioritization according to relaxed physicochem. parameters took place, along with the search for structural analogs. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compds. were subsequently retested in a P. falciparum growth inhibition assay. Results This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compds. progressed to the next steps where chem. diversity, physicochem. properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chem. series. Conclusion A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chem. library against blood-stage P. falciparum. Emphasis was placed on chem. novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochem. filters, were key to the process. This led to the selection of 15 chem. series from which ten confirmed their activity when newly synthesized sample were tested.
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    Bhandari, S. V.; Bothara, K. G.; Patil, A. A.; Chitre, T. S.; Sarkate, A. P.; Gore, S. T. Design, synthesis and pharmacological screening of novel antihypertensive agents using hybrid approach Bioorg. Med. Chem. 2009, 17, 390– 400 DOI: 10.1016/j.bmc.2008.10.032
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    Design, Synthesis and Pharmacological Screening of Novel Antihypertensive Agents Using Hybrid Approach
    Bhandari, Shashikant V.; Bothara, Kailash G.; Patil, Ajit A.; Chitre, Trupti S.; Sarkate, Aniket P.; Gore, Suraj T.; Dangre, Sudarshan C.; Khachane, Chetan V.
    Bioorganic & Medicinal Chemistry (2009), 17 (1), 390-400CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Eight derivs. of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiog., antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compd. 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacol. results suggested that the antiarrhythmic effects of these compds. were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the Ph ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compds. were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compds. 8a-8h were promising enough to continue further expts.
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    Urbano, M.; Guerrero, M.; Velaparthi, S.; Crisp, M.; Chase, P.; Hodder, P. Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype Bioorg. Med. Chem. Lett. 2011, 21, 6739– 6745 DOI: 10.1016/j.bmcl.2011.09.049
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    Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype
    Urbano, Mariangela; Guerrero, Miguel; Velaparthi, Subash; Crisp, Melissa; Chase, Peter; Hodder, Peter; Schaeffer, Marie-Therese; Brown, Steven; Rosen, Hugh; Roberts, Edward
    Bioorganic & Medicinal Chemistry Letters (2011), 21 (22), 6739-6745CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    High affinity and selective S1P4 receptor (S1P4-R) small mol. agonists may be important proof-of-principle tools used to clarify the receptor biol. function and effects to assess the therapeutic potential of the S1P4-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Mol. Libraries-Small Mol. Repository was carried out by our labs. and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one I as a promising S1P4-R agonist hit distinct from literature S1P4-R modulators. Rational chem. modifications of the hit allowed the identification of a promising lead mol. with low nanomolar S1P4-R agonist activity and exquisite selectivity over the other S1P1-3,5-Rs family members. The lead mol. herein disclosed constitutes a valuable pharmacol. tool to explore the effects of the S1P4-R signaling cascade and elucidate the mol. basis of the receptor function.
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    Difference in rate of reaction of some thiazolidinone derivatives with synthesis and spectral characterization
    Singh, Tejprakash; Sharma, Pramod Kumar; Mondal, Sambhu Charan; Kumar, Nitin
    Journal of Advanced Scientific Research (2011), 2 (3), 58-61CODEN: JASRGA; ISSN:0976-9595. (ScienSage)
    Several substituted 5-ethylidene-2-(phenylimino)-4-thiazolidinone derivs. were prepd. by using phenylthiourea as a starting material. Phenylthiourea on reaction with Et chloroacetate in presence of ethanol (95%) and fused sodium acetate gives 2-(phenylimino)-4-thiazolidinone and this compd. furthermore reacts with substituted benzaldehyde gives to provide 5-ethylidene-2-(phenylimino)-4-thiazolidinone derivs. The target compds. thus formed included 5-[(2,4-dinitrophenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone (amine) [or imine, 5-[(2,4-dinitrophenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone], 2-(phenylamino)-5-[(3,4,5-trimethoxyphenyl)methylene]-4(5H)-thiazolone, etc. The reaction products were confirmed on the basis of elemental anal., IR and 1H NMR and Mass spectral anal.
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    Hopkins, A. L.; Keserü, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nat. Rev. Drug Discovery 2014, 13, 105– 121 DOI: 10.1038/nrd4163
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    The role of ligand efficiency metrics in drug discovery
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    Nature Reviews Drug Discovery (2014), 13 (2), 105-121CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. The judicious application of ligand or binding efficiency metrics, which quantify the mol. properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective anal. of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both mol. mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been obsd. in current medicinal chem. practice, and to increase the quality of drug candidates.
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    Baell, J. B.; Holloway, G. A. New substructure filters for removal of Pan Assay Interference Compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719– 2740 DOI: 10.1021/jm901137j
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    New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
    Baell, Jonathan B.; Holloway, Georgina A.
    Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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    Saubern, Simon; Guha, Rajarshi; Baell, Jonathan B.
    Molecular Informatics (2011), 30 (10), 847-850CODEN: MIONBS; ISSN:1868-1743. (Wiley-VCH Verlag GmbH & Co. KGaA)
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    Observations on screening-based research and some concerning trends in the literature
    Baell, Jonathan B.
    Future Medicinal Chemistry (2010), 2 (10), 1529-1546CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    Academic drug discovery is being accompanied by a plethora of publications that report screening hits as good starting points for drug discovery or as useful tool compds., whereas in many cases this is not so. These compds. may be protein-reactive but can also interfere in bioassays via a no. of other means, and it can be very hard to prove early on that they represent false starts. This, for instance, makes it difficult for journals in their assessment of manuscripts submitted for publication. Wider awareness and recognition of these problematic compds. will help the academic drug-discovery community focus on and publish genuinely optimizable screening hits. This will be of general benefit.
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    Mok, N. Y.; Maxe, S.; Brenk, R. Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries J. Chem. Inf. Model. 2013, 53, 534– 544 DOI: 10.1021/ci300382f
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    Locating Sweet Spots for Screening Hits and Evaluating Pan-Assay Interference Filters from the Performance Analysis of Two Lead-like Libraries
    Mok, N. Yi; Maxe, Sara; Brenk, Ruth
    Journal of Chemical Information and Modeling (2013), 53 (3), 534-544CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    The efficiency of automated compd. screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their performance was investigated. Both libraries delivered screening hits across a range of targets, with the hits distributed across the entire chem. space represented by both libraries. On closer inspection, however, hit distribution was uneven across the chem. space, with enrichments obsd. in octants characterized by compds. at the higher end of the mol. wt. and lipophilicity spectrum for lead-like compds., while polar and sp3-carbon atom rich compds. were underrepresented among the screening hits. Based on these observations, we propose that screening libraries should not be evenly distributed in lead-like chem. space but be enriched in polar, aliph. compds. In conjunction with variable concn. screening, this could lead to more balanced hit rates across the chem. space and screening hits of higher ligand efficiency will be captured. Apart from chem. diversity, both screening libraries were shown to be clean from any pan-assay interference (PAINS) behavior. Even though some compds. were flagged to contain PAINS structural motifs, some of these motifs were demonstrated to be less problematic than previously suggested. To maximize the diversity of the chem. space sampled in a screening campaign, we therefore consider it justifiable to retain compds. contg. PAINS structural motifs that were apparently clean in this anal. when assembling screening libraries.
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    Bruns, R. F.; Watson, I. A. Rules for identifying potentially reactive or promiscuous compounds J. Med. Chem. 2012, 55, 9763– 9772 DOI: 10.1021/jm301008n
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    Rules for Identifying Potentially Reactive or Promiscuous Compounds
    Bruns, Robert F.; Watson, Ian A.
    Journal of Medicinal Chemistry (2012), 55 (22), 9763-9772CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    This article describes a set of 275 rules, developed over an 18-yr period, used to identify compds. that may interfere with biol. assays, allowing their removal from screening sets. Reasons for rejection include reactivity (e.g., acyl halides), interference with assay measurements (fluorescence, absorbance, quenching), activities that damage proteins (oxidizers, detergents), instability (e.g., latent aldehydes), and lack of druggability (e.g., compds. lacking both oxygen and nitrogen). The structural queries were profiled for frequency of occurrence in druglike and nondruglike compd. sets and were extensively reviewed by a panel of experienced medicinal chemists. As a means of profiling the rules and as a filter in its own right, an index of biol. promiscuity was developed. The 584 gene targets with screening data at Lilly were assigned to 17 subfamilies, and the no. of subfamilies at which a compd. was active was used as a promiscuity index. For certain compds., promiscuous activity disappeared after sample repurifn., indicating interference from occult contaminants. Because this type of interference is not amenable to substructure search, a "nuisance list" was developed to flag interfering compds. that passed the substructure rules.
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    Mendgen, T.; Steuer, C.; Klein, C. D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry J. Med. Chem. 2012, 55, 743– 753 DOI: 10.1021/jm201243p
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    Privileged Scaffolds or Promiscuous Binders: A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry
    Mendgen, Thomas; Steuer, Christian; Klein, Christian D.
    Journal of Medicinal Chemistry (2012), 55 (2), 743-753CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compds. that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compds. in screening campaigns, we decided to perform a systematic study on their promiscuity. An amt. of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compds. were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compds. in published x-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addn. to other structural features, offers a particularly high d. of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concns. in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compds. and that their exceptional and potentially valuable biomol. binding properties are consequently exploited in a useful way.
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    Thorne, N.; Auld, D. S.; Inglese, J. Apparent activity in high-throughput screening: origins of compound-dependent assay interference Curr. Opin. Chem. Biol. 2010, 14, 315– 324 DOI: 10.1016/j.cbpa.2010.03.020
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    Apparent activity in high-throughput screening: origins of compound-dependent assay interference
    Thorne, Natasha; Auld, Douglas S.; Inglese, James
    Current Opinion in Chemical Biology (2010), 14 (3), 315-324CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    A review. Expansive compd. collections made up of structurally heterogeneous chems., the activities of which are largely undefined, present challenging problems for high-throughput screening (HTS). Foremost is differentiating whether the activity for a given compd. in an assay is directed against the targeted biol., or is the result of surreptitious compd. activity involving the assay detection system. Such compd. interference can be esp. difficult to identify if it is reproducible and concn.-dependent - characteristics generally attributed to compds. with genuine activity. While reactive chem. groups on compds. were once thought to be the primary source of compd. interference in assays used in HTS, recent work suggests that other factors, such as compd. aggregation, may play a more significant role in many assay formats. Considerable progress has been made to profile representative compd. libraries in an effort to identify chem. classes susceptible to producing compd. interference, such as compds. commonly found to inhibit the reporter enzyme firefly luciferase. Such work has also led to the development of practices that have the potential to significantly reduce compd. interference, for example, through the addn. of non-ionic detergent to assay buffer to reduce aggregation-based inhibition.
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    Lowe, D. Polluting the literature with PAINs. In the Pipeline, 2010, http://blogs.sciencemag.org/pipeline/archives/2010/02/08/polluting_the_literature_with_pains, accessed Dec 8, 2015.
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    Singh, Juswinder; Petter, Russell C.; Baillie, Thomas A.; Whitty, Adrian
    Nature Reviews Drug Discovery (2011), 10 (4), 307-317CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. Covalent drugs haveproved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacol. advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.
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    SmartsFilter, http://pasilla.health.unm.edu/tomcat/biocomp/smartsfilter, accessed Dec 8, 2015.
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    Huth, J. R.; Mendoza, R.; Olejniczak, E. T.; Johnson, R. W.; Cothron, D. A.; Liu, Y. ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens J. Am. Chem. Soc. 2005, 127, 217– 224 DOI: 10.1021/ja0455547
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    ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens
    Huth, Jeffrey R.; Mendoza, Renaldo; Olejniczak, Edward T.; Johnson, Robert W.; Cothron, Darlene A.; Liu, Yaya; Lerner, Claude G.; Chen, Jun; Hajduk, Philip J.
    Journal of the American Chemical Society (2005), 127 (1), 217-224CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    High-throughput screening (HTS) of large compd. collections typically results in numerous small mol. hits that must be carefully evaluated to identify valid drug leads. Although several filtering mechanisms and other tools exist that can assist the chemist in this process, it is often the case that costly synthetic resources are expended in pursuing false positives. We report here a rapid and reliable NMR-based method for identifying reactive false positives including those that oxidize or alkylate a protein target. Importantly, the reactive species need not be the parent compd., as both reactive impurities and breakdown products can be detected. The assay is called ALARM NMR (a La assay to detect reactive mols. by NMR) and is based on monitoring DTT-dependent 13C chem. shift changes of the human La antigen in the presence of a test compd. or mixt. Extensive validation has been performed to demonstrate the reliability and utility of using ALARM NMR to assess thiol reactivity. This included comparing ALARM NMR to a glutathione-based fluorescence assay, as well as testing a collection of more than 3500 compds. contg. HTS hits from 23 drug targets. The data show that current in silico filtering tools fail to identify more than half of the compds. that can act via reactive mechanisms. Significantly, we show how ALARM NMR data has been crit. in identifying reactive compds. that would otherwise have been prioritized for lead optimization. In addn., a new filtering tool has been developed on the basis of the ALARM NMR data that can augment current in silico programs for identifying nuisance compds. and improving the process of hit triage.
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  94. 94
    Ekins, S.; Williams, A. J. When pharmaceutical companies publish large datasets: an abundance of riches or fool’s gold? Drug Discovery Today 2010, 15, 812– 815 DOI: 10.1016/j.drudis.2010.08.010
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    When pharmaceutical companies publish large datasets: an abundance of riches or fool's gold?
    Ekins Sean; Williams Antony J
    Drug discovery today (2010), 15 (19-20), 812-5 ISSN:.
    The recent announcement that GlaxoSmithKline have released a huge tranche of whole-cell malaria screening data to the public domain, accompanied by a corresponding publication, raises some issues for consideration before this exemplar instance becomes a trend. We have examined the data from a high level, by studying the molecular properties, and consider the various alerts presently in use by major pharma companies. We not only acknowledge the potential value of such data but also raise the issue of the actual value of such datasets released into the public domain. We also suggest approaches that could enhance the value of such datasets to the community and theoretically offer an immediate benefit to the search for leads for other neglected diseases.
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    OSM Consortium, OSDD Malaria public consultation 1, 2012, https://www.youtube.com/watch?v=ooM8kuo14Bg, accessed Dec 8, 2015, available for download from The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/14110.
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    Todd, M. H. Desired compounds consultation phase 2. Synaptic Leap 2012, Node 412. http://www.thesynapticleap.org/node/412.
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    Ylioja, P. M. Consultation outcome. Synaptic Leap 2012, Node 416. http://www.thesynapticleap.org/node/416.
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    Boström, J.; Hogner, A.; Llinàs, A.; Wellner, E.; Plowright, A. T. Oxadiazoles in medicinal chemistry J. Med. Chem. 2012, 55, 1817– 1830 DOI: 10.1021/jm2013248
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    98
    Oxadiazoles in medicinal chemistry
    Bostrom Jonas; Hogner Anders; Llinas Antonio; Wellner Eric; Plowright Alleyn T
    Journal of medicinal chemistry (2012), 55 (5), 1817-30 ISSN:.
    Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.
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    OSM electronic laboratory notebook, pharmacophore modelling of OSM compounds: http://malaria.ourexperiment.org/pharmacophore_modelling_, accessed Dec 8, 2015.
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    Olesen, P. H. The use of bioisosteric groups in lead optimization Curr. Opin. Drug Discovery Dev. 2001, 4, 471– 478
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    100
    The use of bioisosteric groups in lead optimization
    Olesen, Preben H.
    Current Opinion in Drug Discovery & Development (2001), 4 (4), 471-478CODEN: CODDFF; ISSN:1367-6733. (PharmaPress Ltd.)
    A review with refs. It is now half a century since Friedman introduced the term bioisosterism for the similar biol. activity of structurally related compds. Since then, the concept has been used extensively and successfully in the optimization of lead compds. in drug discovery. The no. of chem. lead compds. has expanded enormously in recent years due to the expression of an increasing no. of recombinant proteins, and the screening of these new protein targets against a large no. of compds. in high-throughput screens. For the fine-tuning of lead compds. to obtain candidates suitable for clin. trials, which is in most circumstances still a tedious process, the use of bioisosteric replacement can be of significant value. This is esp. the case in optimizing for selectivity for a specific target and in improving the pharmacokinetic properties of lead compds. The use of bioisosteres in lead optimization is illustrated by some recent examples from the literature.
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  101. 101
    Open Source Malaria Wiki, GSK Arylpyrrole Series: http://openwetware.org/wiki/OpenSourceMalaria:GSK_Arylpyrrole_Series, accessed Dec 8, 2015. (Snapshot available for download at The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/15389).
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    Berry, L. M.; Wollenberg, L.; Zhao, Z. Esterase activities in the blood, liver and intestine of several preclinical species and humans Drug Metab. Lett. 2009, 3, 70– 77 DOI: 10.2174/187231209788654081
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    102
    Esterase activities in the blood, liver and intestine of several preclinical species and humans
    Berry, Loren M.; Wollenberg, Lance; Zhao, Zhiyang
    Drug Metabolism Letters (2009), 3 (2), 70-77CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)
    Species and tissue differences in the activity of three major classes of esterases, carboxylesterase (CE), butyrylcholinesterase (BChE) and paraoxonase (PON), were studied. Substantial species differences in activity of these esterases were obsd. between the mouse, rat, dog monkey and human. Such species differences must be considered when using these preclin. species to optimize the pharmacokinetic properties of ester compds. intended for human use.
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    Danker, T.; Möller, C. Early identification of hERG liability in drug discovery programs by automated patch clamp Front. Pharmacol. 2014,  DOI: 10.3389/fphar.2014.00203
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    Ruecker, A.; Mathias, D. K.; Straschil, U.; Churcher, T. S.; Dinglasan, R. R.; Leroy, D. A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs Antimicrob. Agents Chemother. 2014, 58, 7292– 7302 DOI: 10.1128/AAC.03666-14
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    104
    A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs
    Ruecker, A.; Mathias, D. K.; Straschil, U.; Churcher, T. S.; Dinglasan, R. R.; Leroy, D.; Sinden, R. E.; Delves, M. J.
    Antimicrobial Agents and Chemotherapy (2014), 58 (12), 7292-7302, 12 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Malaria elimination will require interventions that prevent parasite transmission from the human host to the mosquito. Exptl., this is usually detd. by the expensive and laborious Plasmodium falciparum std. membrane feeding assay (PfSMFA), which has limited utility for high-throughput drug screening. In response, we developed the P. falciparum dual gamete formation assay (PfDGFA), which faithfully simulates the initial stages of the PfSMFA in vitro. It utilizes a dual readout that individually and simultaneously reports on the functional viability of male and female mature stage V gametocytes. To validate, we screen the Medicines for Malaria Venture (MMV) Malaria Box library with the PfDGFA. Unique to this assay, we find compds. that target male gametocytes only and also compds. with reversible and irreversible activity. Most importantly, we show that compd. activity in the PfDGFA accurately predicts activity in PfSMFAs, which validates and supports its adoption into the transmission-stage screening pipeline.
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  105. 105
    Meister, S.; Plouffe, D. M.; Kuhen, K. L.; Bonamy, G. M. C.; Wu, T.; Barnes, S. W. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery Science 2011, 334, 1372– 1377 DOI: 10.1126/science.1211936
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    105
    Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery
    Meister, Stephan; Plouffe, David M.; Kuhen, Kelli L.; Bonamy, Ghislain M. C.; Wu, Tao; Barnes, S. Whitney; Bopp, Selina E.; Borboa, Rachel; Bright, A. Taylor; Che, Jianwei; Cohen, Steve; Dharia, Neekesh V.; Gagaring, Kerstin; Gettayacamin, Montip; Gordon, Perry; Groessl, Todd; Kato, Nobutaka; Lee, Marcus C. S.; McNamara, Case W.; Fidock, David A.; Nagle, Advait; Nam, Tae-gyu; Richmond, Wendy; Roland, Jason; Rottmann, Matthias; Zhou, Bin; Froissard, Patrick; Glynne, Richard J.; Mazier, Dominique; Sattabongkot, Jetsumon; Schultz, Peter G.; Tuntland, Tove; Walker, John R.; Zhou, Yingyao; Chatterjee, Arnab; Diagana, Thierry T.; Winzeler, Elizabeth A.
    Science (Washington, DC, United States) (2011), 334 (6061), 1372-1377CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 com. available compds. with previously demonstrated blood-stage activity (median inhibitory concn. < 1 micromolar) and identified chem. scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compds. active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chem. tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biol. of exo-erythrocytic forms.
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  106. 106
    Lee, A. Y.; St.Onge, R. P.; Proctor, M. J.; Wallace, I. M.; Nile, A. H.; Spagnuolo, P. A. Mapping the cellular response to small molecules using chemogenomic fitness signatures Science 2014, 344, 208– 211 DOI: 10.1126/science.1250217
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    106
    Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures
    Lee, Anna Y.; St. Onge, Robert P.; Proctor, Michael J.; Wallace, Iain M.; Nile, Aaron H.; Spagnuolo, Paul A.; Jitkova, Yulia; Gronda, Marcela; Wu, Yan; Kim, Moshe K.; Cheung-Ong, Kahlin; Torres, Nikko P.; Spear, Eric D.; Han, Mitchell K. L.; Schlecht, Ulrich; Suresh, Sundari; Duby, Geoffrey; Heisler, Lawrence E.; Surendra, Anuradha; Fung, Eula; Urbanus, Malene L.; Gebbia, Marinella; Lissina, Elena; Miranda, Molly; Chiang, Jennifer H.; Aparicio, Ana Maria; Zeghouf, Mahel; Davis, Ronald W.; Cherfils, Jacqueline; Boutry, Marc; Kaiser, Chris A.; Cummins, Carolyn L.; Trimble, William S.; Brown, Grant W.; Schimmer, Aaron D.; Bankaitis, Vytas A.; Nislow, Corey; Bader, Gary D.; Giaever, Guri
    Science (Washington, DC, United States) (2014), 344 (6180), 208-211CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small mols. affects biol. and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compd. in vivo to profile 3250 small mols. in a systematic and unbiased manner. We identified 317 compds. that specifically perturb the function of 121 genes and characterized the mechanism of specific compds. Global anal. revealed that the cellular response to small mols. is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chems., and biol. processes.
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  107. 107
    Subramanian, A.; Tamayo, P.; Mootha, V. K.; Mukherjee, S.; Ebert, B. L.; Gillette, M. A. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 15545– 15550 DOI: 10.1073/pnas.0506580102
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    107
    Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
    Subramanian, Aravind; Tamayo, Pablo; Mootha, Vamsi K.; Mukherjee, Sayan; Ebert, Benjamin L.; Gillette, Michael A.; Paulovich, Amanda; Pomeroy, Scott L.; Golub, Todd R.; Lander, Eric S.; Mesirov, Jill P.
    Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (43), 15545-15550CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Although genomewide RNA expression anal. has become a routine tool in biomedical research, extg. biol. insight from such information remains a major challenge. Here, we describe a powerful anal. method called Gene Set Enrichment Anal. (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, i.e., groups of genes that share common biol. function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene anal. finds little similarity between two independent studies of patients survival in lung cancer, GSEA reveals many biol. pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biol. defined gene sets.
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  108. 108
    Gupta, A. P.; Chin, W. H.; Zhu, L.; Mok, S.; Luah, Y.-H.; Lim, E.-H. Dynamic epigenetic regulation of gene expression during the life cycle of malaria parasite Plasmodium falciparum PLoS Pathog. 2013, 9, e1003170 DOI: 10.1371/journal.ppat.1003170
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    Jiang, L.; Mu, J.; Zhang, Q.; Ni, T.; Srinivasan, P.; Rayavara, K. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum Nature 2013, 499, 223– 227 DOI: 10.1038/nature12361
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    109
    PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum
    Jiang, Lubin; Mu, Jianbing; Zhang, Qingfeng; Ni, Ting; Srinivasan, Prakash; Rayavara, Kempaiah; Yang, Wenjing; Turner, Louise; Lavstsen, Thomas; Theander, Thor G.; Peng, Weiqun; Wei, Guiying; Jing, Qingqing; Wakabayashi, Yoshiyuki; Bansal, Abhisheka; Luo, Yan; Ribeiro, Jose M. C.; Scherf, Artur; Aravind, L.; Zhu, Jun; Zhao, Keji; Miller, Louis H.
    Nature (London, United Kingdom) (2013), 499 (7457), 223-227CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a crit. virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection, the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here, the authors show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an ortholog of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.
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  110. 110
    Yu, L.; Lopez, A.; Anaflous, A.; El Bali, B.; Hamal, A.; Ericson, E. Chemical-genetic profiling of imidazo[1,2-a]pyridines and – pyrimidines reveals target pathways conserved between yeast and human cells PLoS Genet. 2008, 4, e1000284 DOI: 10.1371/journal.pgen.1000284
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    Sanz, L. M.; Crespo, B.; De-Cózar, C.; Ding, X. C.; Llergo, J. L.; Burrows, J. N. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action PLoS One 2012, 7, e30949 DOI: 10.1371/journal.pone.0030949
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    111
    P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action
    Sanz, Laura M.; Crespo, Benigno; De-Cozar, Cristina; Ding, Xavier C.; Llergo, Jose L.; Burrows, Jeremy N.; Garcia-Bustos, Jose F.; Gamo, Francisco-Javier
    PLoS One (2012), 7 (2), e30949CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately det. the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artifacts, as viability and metab. are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compds. on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodol. to measure in vitro the direct effect of antimalarial compds. over the parasite viability, which is based on limiting serial diln. of treated parasites and re-growth monitoring. This methodol. allows to precisely det. the killing rate of antimalarial compds., which can be quantified by the parasite redn. ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to det. compd. killing activities that might be otherwise missed by traditional, metab.-based techniques. The anal. of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compds. based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compds., which are crucially needed for the control and possibly the eradication of malaria.
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  112. 112
    Prathipati, P.; Ma, N. L.; Manjunatha, U. H.; Bender, A. Fishing the target of antitubercular compounds: in silico target deconvolution model development and validation J. Proteome Res. 2009, 8, 2788– 2798 DOI: 10.1021/pr8010843
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    112
    Fishing the Target of Antitubercular Compounds: In Silico Target Deconvolution Model Development and Validation
    Prathipati, Philip; Ma, Ngai Ling; Manjunatha, Ujjini H.; Bender, Andreas
    Journal of Proteome Research (2009), 8 (6), 2788-2798CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    An in silico target prediction protocol for antitubercular (antiTB) compds. has been proposed in this work. This protocol is the extension of a recently published 'domain fishing model' (DFM), validating its predicted targets on a set of 42 common antitubercular drugs. For the 23 antiTB compds. of the set which are directly linked to targets (see text for definition), the DFM exhibited a very good target prediction accuracy of 95%. For 19 compds. indirectly linked to targets also, a reasonable pathway/embedded pathway prediction accuracy of 84% was achieved. Since mostly eukaryotic ligand binding data was used for the DFM generation, the high target prediction accuracy for prokaryotes (which is an extrapolation from the training data) was unexpected and provides an addnl. proof of concept of the DFM. To est. the general applicability of the model, ligand-target coverage anal. was performed. Here, it was found that, although the DFM only modestly covers the entire TB proteome (32% of all proteins), it captures 70% of the proteome subset targeted by 42 common antiTB compds., which is in agreement with the good predictive ability of the DFM for the targets of the compds. chosen here. In a prospective validation, the model successfully predicted the targets of new antiTB compds., CBR-2092 and Amiclenomycin. Together, these findings suggest that in silico target prediction tools may be a useful supplement to existing, exptl. target deconvolution strategies.
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    Koutsoukas, A.; Simms, B.; Kirchmair, J.; Bond, P. J.; Whitmore, A. V.; Zimmer, S. From in silico target prediction to multi-target drug design: current databases, methods and applications J. Proteomics 2011, 74, 2554– 2574 DOI: 10.1016/j.jprot.2011.05.011
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    113
    From in silico target prediction to multi-target drug design: Current databases, methods and applications
    Koutsoukas, Alexios; Simms, Benjamin; Kirchmair, Johannes; Bond, Peter J.; Whitmore, Alan V.; Zimmer, Steven; Young, Malcolm P.; Jenkins, Jeremy L.; Glick, Meir; Glen, Robert C.; Bender, Andreas
    Journal of Proteomics (2011), 74 (12), 2554-2574CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
    A review. Given the tremendous growth of bioactivity databases, the use of computational tools to predict protein targets of small mols. has been gaining importance in recent years. Applications span a wide range, from the designed polypharmacol.' of compds. to mode-of-action anal. In this review, we firstly survey databases that can be used for ligand-based target prediction and which have grown tremendously in size in the past. We furthermore outline methods for target prediction that exist, both based on the knowledge of bioactivities from the ligand side and methods that can be applied in situations when a protein structure is known. Applications of successful in silico target identification attempts are discussed in detail, which were based partly or in whole on computational target predictions in the first instance. This includes the authors' own experience using target prediction tools, in this case considering phenotypic antibacterial screens and the anal. of high-throughput screening data. Finally, we will conclude with the prospective application of databases to not only predict, retrospectively, the protein targets of a small mol., but also how to design ligands with desired polypharmacol. in a prospective manner.
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    Baldwin, J.; Farajallah, A. M.; Malmquist, N. A.; Rathod, P. K.; Phillips, M. A. Malarial dihydroorotate dehydrogenase: substrate and inhibitor specificity J. Biol. Chem. 2002, 277, 41827– 41834 DOI: 10.1074/jbc.M206854200
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    Malarial Dihydroorotate Dehydrogenase
    Baldwin, Jeffrey; Farajallah, Azizeh M.; Malmquist, Nicholas A.; Rathod, Pradipsinh K.; Phillips, Margaret A.
    Journal of Biological Chemistry (2002), 277 (44), 41827-41834CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The malarial parasite relies on de novo pyrimidine biosynthesis to maintain its pyrimidine pools, and unlike the human host cell it is unable to scavenge preformed pyrimidines. Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidn. of dihydroorotate (DHO) to produce orotate, a key step in pyrimidine biosynthesis. The enzyme is located in the outer membrane of the mitochondria of the malarial parasite. To characterize the biochem. properties of the malarial enzyme, an N-terminally truncated version of P. falciparum DHODH has been expressed as a sol., active enzyme in E. coli. The recombinant enzyme binds 0.9 molar equivalents of the cofactor FMN and it has a pH max. of 8.0 (kcat 8 s-1, Km DHO (40-80 μM)). The substrate specificity of the ubiquinone cofactor (CoQn) that is required for the oxidn. of FMN in the second step of the reaction was also detd. The isoprenoid (n) length of CoQn was a determinant of reaction efficiency; CoQ4, CoQ6 and decylubiquinone (CoQD) were efficiently utilized in the reaction while cofactors lacking an isoprenoid tail (CoQ0 and vitamin K3) showed decreased catalytic efficiency, resulting from a 4 to 7-fold increase in K. Five potent inhibitors of mammalian DHODH (Redoxal, dichloroallyl lawsone or DCL, and three analogs of A77 1726) were tested as inhibitors of the malarial enzyme. All five compds. were poor inhibitors of the malarial enzyme, with IC50 values ranging from 0.1-1.0 mM. The IC50 values for inhibition of the malarial enzyme are 102-104-fold higher than the values reported for the mammalian enzyme, demonstrating that inhibitor binding to DHODH is species specific. These studies provide direct evidence that the malarial DHODH active site is different from the host enzyme, and that it is an attractive target for the development of new anti-malarial agents.
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    Spillman, N. J.; Allen, R. J. W.; McNamara, C. W.; Yeung, B. K. S.; Winzeler, E. A.; Diagana, T. T. Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials Cell Host Microbe 2013, 13, 227– 237 DOI: 10.1016/j.chom.2012.12.006
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    116
    Na+ Regulation in the Malaria Parasite Plasmodium falciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials
    Spillman, Natalie J.; Allen, Richard J. W.; McNamara, Case W.; Yeung, Bryan K. S.; Winzeler, Elizabeth A.; Diagana, Thierry T.; Kirk, Kiaran
    Cell Host & Microbe (2013), 13 (2), 227-237CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
    The malaria parasite Plasmodium falciparum establishes in the host erythrocyte plasma membrane new permeability pathways that mediate nutrient uptake into the infected cell. These pathways simultaneously allow Na+ influx, causing [Na+] in the infected erythrocyte cytosol to increase to high levels. The intraerythrocytic parasite itself maintains a low cytosolic [Na+] via unknown mechanisms. Here the authors present evidence that the intraerythrocytic parasite actively extrudes Na+ against an inward gradient via PfATP4, a parasite plasma membrane protein with sequence similarities to Na+-ATPases of lower eukaryotes. Mutations in PfATP4 confer resistance to a potent class of antimalarials, the spiroindolones. Consistent with this, the spiroindolones cause a profound disruption in parasite Na+ homeostasis, which is attenuated in parasites bearing resistance-conferring mutations in PfATP4. The mutant parasites also show some impairment of Na+ regulation. Taken together, the authors' results are consistent with PfATP4 being a Na+ efflux ATPase and a target of the spiroindolones.
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    White, N. J.; Pukrittayakamee, S.; Phyo, A. P.; Rueangweerayut, R.; Nosten, F.; Jittamala, P. Spiroindolone KAE609 for falciparum and vivax malaria N. Engl. J. Med. 2014, 371, 403– 410 DOI: 10.1056/NEJMoa1315860
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    Spiroindolone KAE609 for falciparum and vivax malaria
    White, Nicholas J.; Pukrittayakamee, Sasithon; Phyo, Aung Pyae; Rueangweerayut, Ronnatrai; Nosten, Francois; Jittamala, Podjanee; Jeeyapant, Atthanee; Jain, Jay Prakash; Lefevre, Gilbert; Li, Ruobing; Magnusson, Baldur; Diagana, Thierry T.; Leong, F. Joel
    New England Journal of Medicine (2014), 371 (5), 403-410, 8 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    Background: KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analog with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum. Methods: We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria. The primary end point was the parasite clearance time. Results: The median parasite clearance time was 12 h in each cohort (interquartile range, 8 to 16 h in patients with P. vivax malaria and 10 to 16 h in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 h (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 h (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 h. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 h (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen. Conclusions: KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria.
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    Vaidya, A. B.; Morrisey, J. M.; Zhang, Z.; Das, S.; Daly, T. M.; Otto, T. D. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum Nat. Commun. 2014, 5, 5521 DOI: 10.1038/ncomms6521
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    Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
    Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Inigo; Ferrer, Santiago; Belen Jimenez-Diaz, Maria; Martinez, Maria Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.
    Nature Communications (2014), 5 (), 5521CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    The quest for new antimalarial drugs, esp. those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chem. class of mols., pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compds. A pyrazoleamide compd. causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chem. class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chem. classes.
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    Jiménez-Díaz, M. B.; Ebert, D.; Salinas, Y.; Pradhan, A.; Lehane, A. M.; Myrand-Lapierre, M.-E. +)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E5455– E5462 DOI: 10.1073/pnas.1414221111
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    Flannery, E. L.; McNamara, C. W.; Kim, S. W.; Kato, T. S.; Li, F.-W.; Teng, C. H. Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials ACS Chem. Biol. 2015, 10, 413– 420 DOI: 10.1021/cb500616x
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    120
    Mutations in the P-Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials
    Flannery, Erika L.; McNamara, Case W.; Kim, Sang Wan; Kato, Tomoyo Sakata; Li, Fengwu; Teng, Christine H.; Gagaring, Kerstin; Manary, Micah J.; Barboa, Rachel; Meister, Stephan; Kuhen, Kelli; Vinetz, Joseph M.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.
    ACS Chemical Biology (2015), 10 (2), 413-420CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Aminopyrazoles are a new class of antimalarial compds. identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a crit. role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a crit. antimalarial target.
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    Lehane, A. M.; Ridgway, M. C.; Baker, E.; Kirk, K. Diverse chemotypes disrupt ion homeostasis in the malaria parasite Mol. Microbiol. 2014, 94, 327– 339 DOI: 10.1111/mmi.12765
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    121
    Diverse chemotypes disrupt ion homeostasis in the malaria parasite
    Lehane, Adele M.; Ridgway, Melanie C.; Baker, Eileen; Kirk, Kiaran
    Molecular Microbiology (2014), 94 (2), 327-339CODEN: MOMIEE; ISSN:0950-382X. (Wiley-Blackwell)
    The antimalarial spiroindolones disrupt Plasmodium falciparum Na+ regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP4, a parasite plasma membrane P-type ATPase postulated to export Na+ and import H+ equiv. Here, we screened the 400 antiplasmodial compds. of the open access Malaria Box for their effects on parasite ion regulation. Twenty eight compds. affected parasite Na+ and pH regulation in a manner consistent with PfATP4 inhibition. Six of these, with chem. diverse structures, were selected for further anal. All 6 showed reduced antiplasmodial activity against spiroindolone-resistant parasites carrying mutations in pfatp4. We exposed parasites to incrementally increasing concns. of 2 of the 6 compds. and in both cases obtained resistant parasites with mutations in pfatp4. The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP4 may be a significant Achilles' heel for the parasite.
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    Open Source Malaria Wiki, Triazolopyrazine (TP) Series: http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series, accessed Dec 8, 2015. (Snapshot available for download at The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/15389).
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    van Voorhis, W. C.; Adams, J. H.; Adelfio, R.; Ahyong, V.; Akabas, M. H.; Alano, P. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond PLoS Pathog. 2016, 12, e1005763 DOI: 10.1371/journal.ppat.1005763
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    Open source drug discovery with the malaria box compound collection for neglected diseases and beyond
    Van Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Aleman Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jurgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Cassera, Maria Belen; Cheng, Ken Chih-Chien; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colon-Lopez, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D'Alessandro, Sarah; Dang, Na Le; Delves, Michael; De Risi, Joseph L.; Du, Alan Y.; Duffy, Sandra; El-Sayed, Shimaa Abd El-Salam; Ferdig, Michael T.; Fernandez Robledo, Jose A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Jensen, Amornrat Naranuntarat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinas, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Vera, Iset Medina; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Muller, Joachim; Muriana, Arantza; Hewitt, Stephen Nakazawa; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Rizk, Mohamed Abdo; Ruecker, Andrea; St. Onge, Robert; Ferreira, Rafaela Salgado; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Villela, Filipe Silva; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmuller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Vinh, Phat Voong; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.
    PLoS Pathogens (2016), 12 (7), e1005763/1-e1005763/23CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
    A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biol. is present in universities, whereas the focus of medicinal chem. is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could esp. be bridged through a scale-up of open sharing of phys. compds., which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compds. representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-anal. of the combined dataset. The combined biochem. and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compds. active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addn., many compds. demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicol., pharmacokinetic and metabolic properties were collected on all the compds., assisting in the selection of the most promising candidates for murine proof-of-concept expts. and medicinal chem. programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biol. assays involving human pathogens into drug discovery starting points, by providing open access to new families of mols., and emphasize how a small addnl. investment made to help acquire and distribute compds., and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chem. efforts.
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  • Abstract

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    Figure 1

    Figure 1. Six laws of open research governing the present project.

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    Figure 2

    Figure 2. (A) Arylpyrrole hits from the TCAMS data set. (B) Selected “near neighbors” (NN) from the TCAMS data set. Activities quoted are vs 3D7. Not shown: related NN compounds TCMDC-124456 (680 nM) and TCMDC-125659 (237 nM). (XC50 = approximate IC50 value. (53))

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    Figure 3

    Figure 3. Synthesized amide analogues. Synthetic details and structures of purchased compounds may be found in the Supporting Information. All compounds were found to possess low activity (Table SB2).

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    Figure 4

    Figure 4. Near neighbor compounds biologically evaluated. Raw data may be found in Table SB3.

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    Figure 5

    Figure 5. Analogues evaluated in the main arylpyrrole series.

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    Figure 6

    Figure 6. Three targets that remain open for synthetic inquiry.

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    Figure 7

    Figure 7. Sensitivity of the initial hit OSM-S-5 to minor structural changes.

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    Figure 8

    Figure 8. Closest neighbors of OSM-S-39. (Left) Portion of a network similarity map generated for OSM-S-39 (coded as batch ZYH-72 in the figure) using methods described in the Supporting Information. (Right) The structures (stereochemistry assumed) and potencies (3D7, range if multiple values reported) of the most similar compounds in the ChEMBL database (v13) (key to compound sources: red = GSK TCAMS, blue = Novartis, green = St. Jude’s).

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      BACKGROUND: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border. METHODS: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. FINDINGS: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. INTERPRETATION: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years. FUNDING: The Wellcome Trust and National Institutes of Health.
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      Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure
      Olotu, Ally; Fegan, Gregory; Wambua, Juliana; Nyangweso, George; Awuondo, Ken O.; Leach, Amanda; Lievens, Marc; Leboulleux, Didier; Njuguna, Patricia; Peshu, Norbert; Marsh, Kevin; Bejon, Philip
      New England Journal of Medicine (2013), 368 (12), 1111-1120CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      BACKGROUND: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited. METHODS: For 4 years, we followed children who had been randomly assigned, at 5 to 17 mo of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clin. malaria (temp. of ≥37.5°C and Plasmodium falciparum parasitemia d. of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estd. with the use of the distance-weighted local prevalence of malaria. RESULTS: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clin. malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P = 0.005) and 32.1% (95% CI, 11.6 to 47.8; P = 0.004), resp., calcd. by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, resp.; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P = 0.18) and 24.3% (95% CI, 1.9 to 41.6; P = 0.04), resp., calcd. by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clin. malaria were averted. Vaccine efficacy declined over time (P = 0.004) and with increasing exposure to malaria (P = 0.001) in the per-protocol anal. Vaccine efficacy was 43.6% (95%, CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was av. or lower than av., the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than av. it was 15.9% (95% CI, -11.0 to 36.4). CONCLUSIONS: The efficacy of RTS,S/AS01E vaccine over the 4-yr period was 16.8%. Efficacy declined over time and with increasing malaria exposure.
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    9. 9
      Wells, T. N. C.; van Huijsduijnen, R. H.; Van Voorhis, W. C. Malaria medicines: a glass half full? Nat. Rev. Drug Discovery 2015, 14, 424– 442 DOI: 10.1038/nrd4573
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      9
      Malaria medicines: a glass half full?
      Wells, Timothy N. C.; Hooft van Huijsduijnen, Rob; Van Voorhis, Wesley C.
      Nature Reviews Drug Discovery (2015), 14 (6), 424-442CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compd. or product profiles, to assess progress and gaps, and to recommend priorities.
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    10. 10
      Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A. Antimalarial drug discovery – approaches and progress towards new medicines Nat. Rev. Microbiol. 2013, 11, 849– 862 DOI: 10.1038/nrmicro3138
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      10
      Antimalarial drug discovery - approaches and progress towards new medicines
      Flannery, Erika L.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.
      Nature Reviews Microbiology (2013), 11 (12), 849-862CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
      A review. Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public-private partnerships are funding innovative approaches to identify compds. that target multiple parasite species at multiple stages of the parasite life cycle. In this Review, we discuss the cell-, chem.- and target-based approaches used to discover new drug candidates that are currently in clin. trials or undergoing preclin. testing.
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    11. 11
      Burrows, J. N.; Elliott, R. L.; Kaneko, T.; Mowbray, C. E.; Waterson, D. The role of modern drug discovery in the fight against neglected and tropical diseases MedChemComm 2014, 5, 688– 700 DOI: 10.1039/c4md00011k
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      11
      The role of modern drug discovery in the fight against neglected and tropical diseases
      Burrows, Jeremy N.; Elliott, Richard L.; Kaneko, Takushi; Mowbray, Charles E.; Waterson, David
      MedChemComm (2014), 5 (6), 688-700CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      A review. Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technol. investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chem. diverse compd. libraries to enable lead discovery remains one of the crit. bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
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    12. 12
      Peatey, C. L.; Leroy, D.; Gardiner, D. L.; Trenholme, K. R. Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes? Malar. J. 2012, 11, 34 DOI: 10.1186/1475-2875-11-34
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      12
      Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes?
      Peatey Christopher L; Leroy Didier; Gardiner Donald L; Trenholme Katharine R
      Malaria journal (2012), 11 (), 34 ISSN:.
      BACKGROUND: Recent renewed emphasis on the eradication of malaria has highlighted the need for more tools with which to achieve this ambitious goal. One high priority area is the need to determine the gametocytocidal activity of both currently used anti-malarial drugs and those in the development pipeline. However, testing the activity of compounds against Plasmodium falciparum gametocytes is technically challenging both in vivo and in vitro. METHODS: Here the use of a simple robust assay to screen a panel of currently used and experimental anti-malarial drugs against mature P. falciparum gametocytes is described. RESULTS: Eight of 44 compounds tested reduced gametocyte viability by at least 50% and three showed IC50 values in nM range. CONCLUSIONS: There is a need to identify new compounds with activity against late stage gametocytes and the information provided by this in vitro assay is a valuable first step, which can guide future clinical studies.
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      Duffy, S.; Avery, V. M. Identification of inhibitors of Plasmodium falciparum gametocyte development Malar. J. 2013, 12, 408 DOI: 10.1186/1475-2875-12-408
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      13
      Identification of inhibitors of Plasmodium falciparum gametocyte development
      Duffy, Sandra; Avery, Vicky M.
      Malaria Journal (2013), 12 (), 408/1-408/15, 15 pp.CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
      Background: Plasmodium falciparum gametocytes, specifically mature stages, are the only stage in man transmissible to the mosquito vector responsible for malaria transmission. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria. The comprehensive profiling of in vitro activity of anti-malarial compds. against both early (I-III) and late (IV-V) stage P. falciparum gametocytes, along with the high throughput screening (HTS) outcomes from the MMV malaria box are described. Method: Two anti-gametocyte HTS assays based on confocal fluorescence microscopy, utilizing both a gametocyte specific protein (pfs16-Luc-GFP) and a viability marker (MitoTracker Red CM-H2XRos) (MTR), were used for the measurement of anti-gametocytocidal activity. This combination provided a direct observation of gametocyte no. per assay well, while defining the viability of each gametocyte imaged. Results: IC50 values were obtained for 36 current anti-malarial compds. for activities against asexual, early and late stage gametocytes. The MMV malaria box was screened and actives progressed for IC50 evaluation. Seven % of the "drug-like" and 21% of the "probe-like" compds. from the MMV malaria box demonstrated equiv. activity against both asexual and late stage gametocytes. Conclusions: The assays described were shown to selectively identify compds. with gametocytocidal activity and have been demonstrated suitable for HTS with the capability of screening in the order of 20,000 compds. per screening campaign, two to three times per seven-day week.
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      McNamara, C. W.; Lee, M. C. S.; Lim, C. S.; Lim, S. H.; Roland, J.; Nagle, A. Targeting Plasmodium PI(4)K to eliminate malaria Nature 2013, 504, 248– 253 DOI: 10.1038/nature12782
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      Targeting Plasmodium PI(4)K to eliminate malaria
      McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.
      Nature (London, United Kingdom) (2013), 504 (7479), 248-253CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here the authors identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compd. class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. The authors show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, the authors' data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
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      Dembélé, L.; Franetich, J.-F.; Lorthiois, A.; Gego, A.; Zeeman, A.-M.; Kocken, C. H. M. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures Nat. Med. 2014, 20, 307– 312 DOI: 10.1038/nm.3461
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      Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures
      Dembele, Laurent; Franetich, Jean-Francois; Lorthiois, Audrey; Gego, Audrey; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Le Grand, Roger; Dereuddre-Bosquet, Nathalie; van Gemert, Geert-Jan; Sauerwein, Robert; Vaillant, Jean-Christophe; Hannoun, Laurent; Fuchter, Matthew J.; Diagana, Thierry T.; Malmquist, Nicholas A.; Scherf, Artur; Snounou, Georges; Mazier, Dominique
      Nature Medicine (New York, NY, United States) (2014), 20 (3), 307-312CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compds. that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, exptl. infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept expt., we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biol. and the search for compds. that kill hypnozoites or disrupt their quiescence.
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      Scannell, J. W.; Blanckley, A.; Boldon, H.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency Nat. Rev. Drug Discovery 2012, 11, 191– 200 DOI: 10.1038/nrd3681
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      Diagnosing the decline in pharmaceutical R&D efficiency
      Scannell, Jack W.; Blanckley, Alex; Boldon, Helen; Warrington, Brian
      Nature Reviews Drug Discovery (2012), 11 (3), 191-200CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. The past 60 years have seen huge advances in many of the scientific, technol. and managerial factors that should tend to raise the efficiency of com. drug research and development (RD). Yet the no. of new drugs approved per billion US dollars spent on RD has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solns. to the problem of declining RD efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the no. of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research-brute force' bias. Our aim is to provoke a more systematic anal. of the causes of the decline in RD efficiency.
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      Paul, S. M.; Mytelka, D. S.; Dunwiddie, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R. How to improve R&D productivity: the pharmaceutical industry’s grand challenge Nat. Rev. Drug Discovery 2010, 9, 203– 214 DOI: 10.1038/nrd3078
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      How to improve R&D productivity: the pharmaceutical industry's grand challenge
      Paul, Steven M.; Mytelka, Daniel S.; Dunwiddie, Christopher T.; Persinger, Charles C.; Munos, Bernard H.; Lindborg, Stacy R.; Schacht, Aaron L.
      Nature Reviews Drug Discovery (2010), 9 (3), 203-214CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the no. and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a no. of years. Here, we present a detailed anal. based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.
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      Jakobsen, P. H.; Wang, M.-W.; Nwaka, S. Innovative partnerships for drug discovery against neglected diseases PLoS Neglected Trop. Dis. 2011, 5, e1221 DOI: 10.1371/journal.pntd.0001221
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      Lotharius, J.; Gamo-Benito, F. J.; Angulo-Barturen, I.; Clark, J.; Connelly, M.; Ferrer-Bazaga, S. Repositioning: the fast track to new anti-malarial medicines? Malar. J. 2014, 13, 143 DOI: 10.1186/1475-2875-13-143
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      Repositioning: the fast track to new anti-malarial medicines?
      Lotharius Julie; Gamo-Benito Francisco Javier; Angulo-Barturen Inigo; Clark Julie; Connelly Michele; Ferrer-Bazaga Santiago; Parkinson Tanya; Viswanath Pavithra; Bandodkar Balachandra; Rautela Nikhil; Bharath Sowmya; Duffy Sandra; Avery Vicky M; Guy R Kiplin; Wells Timothy; Mohrle Jorg J
      Malaria journal (2014), 13 (), 143 ISSN:.
      BACKGROUND: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. METHODS: Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [(3)H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model. RESULTS: Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model. CONCLUSIONS: Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at μM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
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      Munos, B. Can open-source drug R&D repower pharmaceutical innovation? Clin. Pharmacol. Ther. 2010, 87, 534– 536 DOI: 10.1038/clpt.2010.26
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      Can open-source drug R&D repower pharmaceutical innovation?
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      Clinical pharmacology and therapeutics (2010), 87 (5), 534-6 ISSN:.
      Open-source R&D initiatives are multiplying across biomedical research. Some of them-such as public-private partnerships-have achieved notable success in bringing new drugs to market economically, whereas others reflect the pharmaceutical industry's efforts to retool its R&D model. Is open innovation the answer to the innovation crisis? This Commentary argues that although it may likely be part of the solution, significant cultural, scientific, and regulatory barriers can prevent it from delivering on its promise.
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      Woelfle, M.; Olliaro, P.; Todd, M. H. Open science is a research accelerator Nat. Chem. 2011, 3, 745– 748 DOI: 10.1038/nchem.1149
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      Open science is a research accelerator
      Woelfle, Michael; Olliaro, Piero; Todd, Matthew H.
      Nature Chemistry (2011), 3 (10), 745-748CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      A review with commentary. An open-source approach to the problem of producing an off-patent drug in enantiopure form serves as an example of how academic and industrial researchers can join forces to make new scientific discoveries that could have a huge impact on human health.
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      Ortí, L.; Carbajo, R. J.; Pieper, U.; Eswar, N.; Maurer, S. M.; Rai, A. K. A kernel for open source drug discovery in tropical diseases PLoS Neglected Trop. Dis. 2009, 3, e418 DOI: 10.1371/journal.pntd.0000418
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      Årdal, C.; Alstadsæter, A.; Røttingen, J. A. Common characteristics of open source software development and applicability for drug discovery: a systematic review Health Res. Policy Syst. 2011, 9, 36 DOI: 10.1186/1478-4505-9-36
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      Common characteristics of open source software development and applicability for drug discovery: a systematic review
      Ardal Christine; Alstadsaeter Annette; Rottingen John-Arne
      Health research policy and systems / BioMed Central (2011), 9 (), 36 ISSN:.
      BACKGROUND: Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. METHODS: A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. RESULTS: Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. CONCLUSIONS: We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.
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      DeLano, W. L. The case for open-source software in drug discovery Drug Discovery Today 2005, 10, 213– 217 DOI: 10.1016/S1359-6446(04)03363-X
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      The case for open-source software in drug discovery
      DeLano, Warren L.
      Drug Discovery Today (2005), 10 (3), 213-217CODEN: DDTOFS; ISSN:1359-6446. (Elsevier)
      A review. Widespread adoption of open-source software for network infrastructure, web servers, code development, and operating systems leads one to ask how far it can go. Will open source' spread broadly, or will it be restricted to niches frequented by hopeful hobbyists and midnight hackers Here we identify reasons for the success of open-source software and predict how consumers in drug discovery will benefit from new open-source products that address their needs with increased flexibility and in ways complementary to proprietary options.
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      Woelfle, M.; Seerden, J.-P.; de Gooijer, J.; Pouwer, K.; Olliaro, P.; Todd, M. H. Resolution of praziquantel PLoS Neglected Trop. Dis. 2011, 5, e1260 DOI: 10.1371/journal.pntd.0001260
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      Resolution of praziquantel
      Woelfle, Michael; Seerden, Jean-Paul; de Gooijer, Jesse; Pouwer, Kees; Olliaro, Piero; Todd, Matthew H.
      PLoS Neglected Tropical Diseases (2011), 5 (9), e1260CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
      Background: Praziquantel remains the drug of choice for the worldwide treatment and control of schistosomiasis. The drug is synthesized and administered as a racemate. Use of the pure active enantiomer would be desirable since the inactive enantiomer is assocd. with side effects and is responsible for the extremely bitter taste of the pill. Methodol./Principal Findings: We have identified two resoln. approaches toward the prodn. of praziquantel as a single enantiomer. One approach starts with com. available praziquantel and involves a hydrolysis to an intermediate amine, which is resolved with a deriv. of tartaric acid. This method was discovered through an open collaboration on the internet. The second method, identified by a contract research organization, employs a different intermediate that may be resolved with tartaric acid itself. Conclusions/Significance: Both resoln. procedures identified show promise for the large-scale, economically viable prodn. of praziquantel as a single enantiomer for a low price. Addnl., they may be employed by labs. for the prodn. of smaller amts. of enantiopure drug for research purposes that should be useful in, for example, elucidation of the drug's mechanism of action.
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      Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells
      Reaves, Marshall Louis; Sinha, Sunita; Rabinowitz, Joshua D.; Kruglyak, Leonid; Redfield, Rosemary J.
      Science (Washington, DC, United States) (2012), 337 (6093), 470-473CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A strain of Halomonas bacteria, GFAJ-1, has been claimed to be able to use arsenate as a nutrient when phosphate is limiting and to specifically incorporate arsenic into its DNA in place of phosphorus. However, the authors have found that arsenate does not contribute to growth of GFAJ-1 when phosphate is limiting and that DNA purified from cells grown with limiting phosphate and abundant arsenate does not exhibit the spontaneous hydrolysis expected of arsenate ester bonds. Furthermore, mass spectrometry showed that this DNA contains only trace amts. of free arsenate and no detectable covalently bound arsenate.
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      New England Journal of Medicine (2013), 368 (9), 789-791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
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      Badiola, K. A.; Bird, C.; Brocklesby, W. S.; Casson, J.; Chapman, R. T.; Coles, S. J. Experiences with a researcher-centric ELN Chem. Sci. 2015, 6, 1614– 1629 DOI: 10.1039/C4SC02128B
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      Chemical Science (2015), 6 (3), 1614-1629CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A review. Electronic Lab. Notebooks (ELNs) are progressively replacing traditional paper books in both com. research establishments and academic institutions. University researchers require specific features from ELNs, given the need to promote cross-institutional collaborative working, to enable the sharing of procedures and results, and to facilitate publication. The LabTrove ELN, which we use as our exemplar, was designed to be researcher-centric (i.e., not only aimed at the individual researcher's basic needs rather than to a specific institutional or subject or disciplinary agenda, but also able to be tailored because it is open source). LabTrove is being used in a heterogeneous set of academic labs., for a range of purposes, including anal. chem., X-ray studies, drug discovery and a biomaterials project. Researchers use the ELN for recording expts., preserving data collected, and for project coordination. This perspective article describes the experiences of those researchers from several viewpoints, demonstrating how a web-based open source electronic notebook can meet the diverse needs of academic researchers.
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      Gamo, F.-J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.-L. Thousands of chemical starting points for antimalarial lead identification Nature 2010, 465, 305– 310 DOI: 10.1038/nature09107
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      Thousands of chemical starting points for antimalarial lead identification
      Gamo, Francisco-Javier; Sanz, Laura M.; Vidal, Jaume; de Cozar, Cristina; Alvarez, Emilio; Lavandera, Jose-Luis; Vanderwall, Dana E.; Green, Darren V. S.; Kumar, Vinod; Hasan, Samiul; Brown, James R.; Peishoff, Catherine E.; Cardon, Lon R.; Garcia-Bustos, Jose F.
      Nature (London, United Kingdom) (2010), 465 (7296), 305-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chem. class of antimalarials has been introduced into clin. practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compds. in GlaxoSmithKline's chem. library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 μM concn. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compds. originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chem. structures and assocd. data are hereby made public to encourage addnl. drug lead identification efforts and further research into this disease.
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      Guiguemde, W. A.; Shelat, A. A.; Bouck, D.; Duffy, S.; Crowther, G. J.; Davis, P. H. Chemical genetics of Plasmodium falciparum Nature 2010, 465, 311– 315 DOI: 10.1038/nature09099
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      Chemical genetics of Plasmodium falciparum
      Guiguemde, W. Armand; Shelat, Anang A.; Bouck, David; Duffy, Sandra; Crowther, Gregory J.; Davis, Paul H.; Smithson, David C.; Connelly, Michele; Clark, Julie; Zhu, Fangyi; Jimenez-Diaz, Maria B.; Martinez, Maria S.; Wilson, Emily B.; Tripathi, Abhai K.; Gut, Jiri; Sharlow, Elizabeth R.; Bathurst, Ian; El Mazouni, Farah; Fowble, Joseph W.; Forquer, Isaac; McGinley, Paula L.; Castro, Steve; Angulo-Barturen, Inigo; Ferrer, Santiago; Rosenthal, Philip J.; De Risi, Joseph L.; Sullivan, David J., Jr.; Lazo, John S.; Roos, David S.; Riscoe, Michael K.; Phillips, Margaret A.; Rathod, Pradipsinh K.; Van Voorhis, Wesley C.; Avery, Vicky M.; Guy, R. Kiplin
      Nature (London, United Kingdom) (2010), 465 (7296), 311-315CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per yr worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chem. genetic approach to assay 309,474 chems. Here we disclose structures and biol. activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chem. genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compd. displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
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      Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 9059– 9064 DOI: 10.1073/pnas.0802982105
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      In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen
      Plouffe, David; Brinker, Achim; McNamara, Case; Henson, Kerstin; Kato, Nobutaka; Kuhen, Kelli; Nagle, Advait; Adrian, Francisco; Matzen, Jason T.; Anderson, Paul; Nam, Tae-gyu; Gray, Nathanael S.; Chatterjee, Arnab; Janes, Jeff; Yan, S. Frank; Trager, Richard; Caldwell, Jeremy S.; Schultz, Peter G.; Zhou, Yingyao; Winzeler, Elizabeth A.
      Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (26), 9059-9064CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈ 1.7 million compds., we identified a diverse collection of ≈ 6,000 small mols. comprised of > 530 distinct scaffolds, all of which show potent antimalarial activity (< 1.25 μM). Most known antimalarials were identified in this screen, thus validating our approach. In addn., we identified many novel chem. scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be detd. by in silico compd. activity profiling. This method uses large datasets from unrelated cellular and biochem. screens and the guilt-by-assocn. principle to predict which cellular pathway and/or protein target is being inhibited by select compds. In addn., the screening method has the potential to provide the malaria community with many new starting points for the development of biol. probes and drugs with novel antiparasitic activities.
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      Calderón, F.; Barros, D.; Bueno, J. M.; Coterón, J. M.; Fernández, E.; Gamo, F. J. An invitation to open innovation in malaria drug discovery: 47 quality starting points from the TCAMS ACS Med. Chem. Lett. 2011, 2, 741– 746 DOI: 10.1021/ml200135p
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      An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS
      Calderon, Felix; Barros, David; Bueno, Jose Maria; Coteron, Jose Miguel; Fernandez, Esther; Gamo, Francisco Javier; Lavandera, Jose Luis; Leon, Maria Luisa; MacDonald, Simon J. F.; Mallo, Araceli; Manzano, Pilar; Porras, Esther; Fiandor, Jose Maria; Castro, Julia
      ACS Medicinal Chemistry Letters (2011), 2 (10), 741-746CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      In 2010, GlaxoSmithKline published the structures of 13533 chem. starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochem. properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clin. candidates.
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      Rueda, L.; Castellote, I.; Castro-Pichel, J.; Chaparro, M. J.; de la Rosa, J. C.; Garcia-Perez, A. Cyclopropyl carboxamides: a new oral antimalarial series derived from the Tres Cantos anti-malarial set (TCAMS) ACS Med. Chem. Lett. 2011, 2, 840– 844 DOI: 10.1021/ml2001517
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      Discovery and Structure-Activity Relationships of Pyrrolone Antimalarials
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      In the pursuit of new antimalarial leads, a phenotypic screening of various com. sourced compd. libraries was undertaken by the World Health Organization Program for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (I), which showed potent activity against Plasmodium falciparum K1 (EC50 ∼ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered i.p. Structure-activity relationship studies have indicated ways in which the mol. could be optimized. This compd. represents an exciting start point for a drug discovery program for the development of a novel antimalarial.
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      Avery, Vicky M.; Bashyam, Sridevi; Burrows, Jeremy N.; Duffy, Sandra; Papadatos, George; Puthukkuti, Shyni; Sambandan, Yuvaraj; Singh, Shivendra; Spangenberg, Thomas; Waterson, David; Willis, Paul
      Malaria Journal (2014), 13 (), 190/1-190/26, 26CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)
      Background In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e g, new modes of action, transmission-blocking activity or long-duration chemo-protection), a chem. library consisting of more than 250,000 compds. has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chem. diversity and novelty. Methods The selection cascade used for the triaging of hits from the chem. library started with a robust three-step in vitro assay followed by an in silico anal. of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational anal. to assess chem. properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chem. space defined by the hits. Then, in cerebro evaluation of the chem. structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chem. programs. Next, prioritization according to relaxed physicochem. parameters took place, along with the search for structural analogs. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compds. were subsequently retested in a P. falciparum growth inhibition assay. Results This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compds. progressed to the next steps where chem. diversity, physicochem. properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chem. series. Conclusion A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chem. library against blood-stage P. falciparum. Emphasis was placed on chem. novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochem. filters, were key to the process. This led to the selection of 15 chem. series from which ten confirmed their activity when newly synthesized sample were tested.
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      Open Source Malaria Google+ Community, https://plus.google.com/114702323662314783325/posts/Pma1Ddk2XCy, 2012, accessed Dec 8, 2015.
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      Bhandari, S. V.; Bothara, K. G.; Patil, A. A.; Chitre, T. S.; Sarkate, A. P.; Gore, S. T. Design, synthesis and pharmacological screening of novel antihypertensive agents using hybrid approach Bioorg. Med. Chem. 2009, 17, 390– 400 DOI: 10.1016/j.bmc.2008.10.032
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      Design, Synthesis and Pharmacological Screening of Novel Antihypertensive Agents Using Hybrid Approach
      Bhandari, Shashikant V.; Bothara, Kailash G.; Patil, Ajit A.; Chitre, Trupti S.; Sarkate, Aniket P.; Gore, Suraj T.; Dangre, Sudarshan C.; Khachane, Chetan V.
      Bioorganic & Medicinal Chemistry (2009), 17 (1), 390-400CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Eight derivs. of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiog., antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compd. 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacol. results suggested that the antiarrhythmic effects of these compds. were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the Ph ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compds. were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compds. 8a-8h were promising enough to continue further expts.
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      Urbano, M.; Guerrero, M.; Velaparthi, S.; Crisp, M.; Chase, P.; Hodder, P. Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype Bioorg. Med. Chem. Lett. 2011, 21, 6739– 6745 DOI: 10.1016/j.bmcl.2011.09.049
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      Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype
      Urbano, Mariangela; Guerrero, Miguel; Velaparthi, Subash; Crisp, Melissa; Chase, Peter; Hodder, Peter; Schaeffer, Marie-Therese; Brown, Steven; Rosen, Hugh; Roberts, Edward
      Bioorganic & Medicinal Chemistry Letters (2011), 21 (22), 6739-6745CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      High affinity and selective S1P4 receptor (S1P4-R) small mol. agonists may be important proof-of-principle tools used to clarify the receptor biol. function and effects to assess the therapeutic potential of the S1P4-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Mol. Libraries-Small Mol. Repository was carried out by our labs. and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one I as a promising S1P4-R agonist hit distinct from literature S1P4-R modulators. Rational chem. modifications of the hit allowed the identification of a promising lead mol. with low nanomolar S1P4-R agonist activity and exquisite selectivity over the other S1P1-3,5-Rs family members. The lead mol. herein disclosed constitutes a valuable pharmacol. tool to explore the effects of the S1P4-R signaling cascade and elucidate the mol. basis of the receptor function.
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      Singh, T.; Sharma, P. K.; Mondal, S. C.; Kumar, N. Difference in rate of reaction of some thiazolidinone derivatives with synthesis and spectral characterization J. Adv. Sci. Res. 2011, 2, 58– 61
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      Difference in rate of reaction of some thiazolidinone derivatives with synthesis and spectral characterization
      Singh, Tejprakash; Sharma, Pramod Kumar; Mondal, Sambhu Charan; Kumar, Nitin
      Journal of Advanced Scientific Research (2011), 2 (3), 58-61CODEN: JASRGA; ISSN:0976-9595. (ScienSage)
      Several substituted 5-ethylidene-2-(phenylimino)-4-thiazolidinone derivs. were prepd. by using phenylthiourea as a starting material. Phenylthiourea on reaction with Et chloroacetate in presence of ethanol (95%) and fused sodium acetate gives 2-(phenylimino)-4-thiazolidinone and this compd. furthermore reacts with substituted benzaldehyde gives to provide 5-ethylidene-2-(phenylimino)-4-thiazolidinone derivs. The target compds. thus formed included 5-[(2,4-dinitrophenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone (amine) [or imine, 5-[(2,4-dinitrophenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone], 2-(phenylamino)-5-[(3,4,5-trimethoxyphenyl)methylene]-4(5H)-thiazolone, etc. The reaction products were confirmed on the basis of elemental anal., IR and 1H NMR and Mass spectral anal.
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      Hopkins, A. L.; Keserü, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nat. Rev. Drug Discovery 2014, 13, 105– 121 DOI: 10.1038/nrd4163
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      The role of ligand efficiency metrics in drug discovery
      Hopkins, Andrew L.; Keserue, Gyoergy M.; Leeson, Paul D.; Rees, David C.; Reynolds, Charles H.
      Nature Reviews Drug Discovery (2014), 13 (2), 105-121CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. The judicious application of ligand or binding efficiency metrics, which quantify the mol. properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective anal. of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both mol. mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been obsd. in current medicinal chem. practice, and to increase the quality of drug candidates.
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      Todd, M. H. Biological results for first set of compounds. Synaptic Leap 2012, Node 367. http://www.thesynapticleap.org/node/367.
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      Baell, J. B.; Holloway, G. A. New substructure filters for removal of Pan Assay Interference Compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719– 2740 DOI: 10.1021/jm901137j
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      New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
      Baell, Jonathan B.; Holloway, Georgina A.
      Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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      Saubern, S.; Guha, R.; Baell, J. B. KNIME workflow to assess PAINS filters in SMARTS format. Comparison of RDKit and Indigo cheminformatics libraries Mol. Inf. 2011, 30, 847– 850 DOI: 10.1002/minf.201100076
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      KNIME Workflow to Assess PAINS Filters in SMARTS Format. Comparison of RDKit and Indigo Cheminformatics Libraries
      Saubern, Simon; Guha, Rajarshi; Baell, Jonathan B.
      Molecular Informatics (2011), 30 (10), 847-850CODEN: MIONBS; ISSN:1868-1743. (Wiley-VCH Verlag GmbH & Co. KGaA)
      There is no expanded citation for this reference.
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      Baell, J. B. Observations on screening-based research and some concerning trends in the literature Future Med. Chem. 2010, 2, 1529– 1546 DOI: 10.4155/fmc.10.237
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      Observations on screening-based research and some concerning trends in the literature
      Baell, Jonathan B.
      Future Medicinal Chemistry (2010), 2 (10), 1529-1546CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      Academic drug discovery is being accompanied by a plethora of publications that report screening hits as good starting points for drug discovery or as useful tool compds., whereas in many cases this is not so. These compds. may be protein-reactive but can also interfere in bioassays via a no. of other means, and it can be very hard to prove early on that they represent false starts. This, for instance, makes it difficult for journals in their assessment of manuscripts submitted for publication. Wider awareness and recognition of these problematic compds. will help the academic drug-discovery community focus on and publish genuinely optimizable screening hits. This will be of general benefit.
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      Mok, N. Y.; Maxe, S.; Brenk, R. Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries J. Chem. Inf. Model. 2013, 53, 534– 544 DOI: 10.1021/ci300382f
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      Locating Sweet Spots for Screening Hits and Evaluating Pan-Assay Interference Filters from the Performance Analysis of Two Lead-like Libraries
      Mok, N. Yi; Maxe, Sara; Brenk, Ruth
      Journal of Chemical Information and Modeling (2013), 53 (3), 534-544CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      The efficiency of automated compd. screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their performance was investigated. Both libraries delivered screening hits across a range of targets, with the hits distributed across the entire chem. space represented by both libraries. On closer inspection, however, hit distribution was uneven across the chem. space, with enrichments obsd. in octants characterized by compds. at the higher end of the mol. wt. and lipophilicity spectrum for lead-like compds., while polar and sp3-carbon atom rich compds. were underrepresented among the screening hits. Based on these observations, we propose that screening libraries should not be evenly distributed in lead-like chem. space but be enriched in polar, aliph. compds. In conjunction with variable concn. screening, this could lead to more balanced hit rates across the chem. space and screening hits of higher ligand efficiency will be captured. Apart from chem. diversity, both screening libraries were shown to be clean from any pan-assay interference (PAINS) behavior. Even though some compds. were flagged to contain PAINS structural motifs, some of these motifs were demonstrated to be less problematic than previously suggested. To maximize the diversity of the chem. space sampled in a screening campaign, we therefore consider it justifiable to retain compds. contg. PAINS structural motifs that were apparently clean in this anal. when assembling screening libraries.
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      Bruns, R. F.; Watson, I. A. Rules for identifying potentially reactive or promiscuous compounds J. Med. Chem. 2012, 55, 9763– 9772 DOI: 10.1021/jm301008n
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      Rules for Identifying Potentially Reactive or Promiscuous Compounds
      Bruns, Robert F.; Watson, Ian A.
      Journal of Medicinal Chemistry (2012), 55 (22), 9763-9772CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      This article describes a set of 275 rules, developed over an 18-yr period, used to identify compds. that may interfere with biol. assays, allowing their removal from screening sets. Reasons for rejection include reactivity (e.g., acyl halides), interference with assay measurements (fluorescence, absorbance, quenching), activities that damage proteins (oxidizers, detergents), instability (e.g., latent aldehydes), and lack of druggability (e.g., compds. lacking both oxygen and nitrogen). The structural queries were profiled for frequency of occurrence in druglike and nondruglike compd. sets and were extensively reviewed by a panel of experienced medicinal chemists. As a means of profiling the rules and as a filter in its own right, an index of biol. promiscuity was developed. The 584 gene targets with screening data at Lilly were assigned to 17 subfamilies, and the no. of subfamilies at which a compd. was active was used as a promiscuity index. For certain compds., promiscuous activity disappeared after sample repurifn., indicating interference from occult contaminants. Because this type of interference is not amenable to substructure search, a "nuisance list" was developed to flag interfering compds. that passed the substructure rules.
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      Mendgen, T.; Steuer, C.; Klein, C. D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry J. Med. Chem. 2012, 55, 743– 753 DOI: 10.1021/jm201243p
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      Privileged Scaffolds or Promiscuous Binders: A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry
      Mendgen, Thomas; Steuer, Christian; Klein, Christian D.
      Journal of Medicinal Chemistry (2012), 55 (2), 743-753CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compds. that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compds. in screening campaigns, we decided to perform a systematic study on their promiscuity. An amt. of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compds. were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compds. in published x-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addn. to other structural features, offers a particularly high d. of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concns. in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compds. and that their exceptional and potentially valuable biomol. binding properties are consequently exploited in a useful way.
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      Thorne, N.; Auld, D. S.; Inglese, J. Apparent activity in high-throughput screening: origins of compound-dependent assay interference Curr. Opin. Chem. Biol. 2010, 14, 315– 324 DOI: 10.1016/j.cbpa.2010.03.020
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      Apparent activity in high-throughput screening: origins of compound-dependent assay interference
      Thorne, Natasha; Auld, Douglas S.; Inglese, James
      Current Opinion in Chemical Biology (2010), 14 (3), 315-324CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      A review. Expansive compd. collections made up of structurally heterogeneous chems., the activities of which are largely undefined, present challenging problems for high-throughput screening (HTS). Foremost is differentiating whether the activity for a given compd. in an assay is directed against the targeted biol., or is the result of surreptitious compd. activity involving the assay detection system. Such compd. interference can be esp. difficult to identify if it is reproducible and concn.-dependent - characteristics generally attributed to compds. with genuine activity. While reactive chem. groups on compds. were once thought to be the primary source of compd. interference in assays used in HTS, recent work suggests that other factors, such as compd. aggregation, may play a more significant role in many assay formats. Considerable progress has been made to profile representative compd. libraries in an effort to identify chem. classes susceptible to producing compd. interference, such as compds. commonly found to inhibit the reporter enzyme firefly luciferase. Such work has also led to the development of practices that have the potential to significantly reduce compd. interference, for example, through the addn. of non-ionic detergent to assay buffer to reduce aggregation-based inhibition.
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      Lowe, D. Polluting the literature with PAINs. In the Pipeline, 2010, http://blogs.sciencemag.org/pipeline/archives/2010/02/08/polluting_the_literature_with_pains, accessed Dec 8, 2015.
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      Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. The resurgence of covalent drugs Nat. Rev. Drug Discovery 2011, 10, 307– 317 DOI: 10.1038/nrd3410
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      The resurgence of covalent drugs
      Singh, Juswinder; Petter, Russell C.; Baillie, Thomas A.; Whitty, Adrian
      Nature Reviews Drug Discovery (2011), 10 (4), 307-317CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Covalent drugs haveproved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacol. advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.
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      Huth, J. R.; Mendoza, R.; Olejniczak, E. T.; Johnson, R. W.; Cothron, D. A.; Liu, Y. ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens J. Am. Chem. Soc. 2005, 127, 217– 224 DOI: 10.1021/ja0455547
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      ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens
      Huth, Jeffrey R.; Mendoza, Renaldo; Olejniczak, Edward T.; Johnson, Robert W.; Cothron, Darlene A.; Liu, Yaya; Lerner, Claude G.; Chen, Jun; Hajduk, Philip J.
      Journal of the American Chemical Society (2005), 127 (1), 217-224CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      High-throughput screening (HTS) of large compd. collections typically results in numerous small mol. hits that must be carefully evaluated to identify valid drug leads. Although several filtering mechanisms and other tools exist that can assist the chemist in this process, it is often the case that costly synthetic resources are expended in pursuing false positives. We report here a rapid and reliable NMR-based method for identifying reactive false positives including those that oxidize or alkylate a protein target. Importantly, the reactive species need not be the parent compd., as both reactive impurities and breakdown products can be detected. The assay is called ALARM NMR (a La assay to detect reactive mols. by NMR) and is based on monitoring DTT-dependent 13C chem. shift changes of the human La antigen in the presence of a test compd. or mixt. Extensive validation has been performed to demonstrate the reliability and utility of using ALARM NMR to assess thiol reactivity. This included comparing ALARM NMR to a glutathione-based fluorescence assay, as well as testing a collection of more than 3500 compds. contg. HTS hits from 23 drug targets. The data show that current in silico filtering tools fail to identify more than half of the compds. that can act via reactive mechanisms. Significantly, we show how ALARM NMR data has been crit. in identifying reactive compds. that would otherwise have been prioritized for lead optimization. In addn., a new filtering tool has been developed on the basis of the ALARM NMR data that can augment current in silico programs for identifying nuisance compds. and improving the process of hit triage.
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      Ekins, S.; Williams, A. J. When pharmaceutical companies publish large datasets: an abundance of riches or fool’s gold? Drug Discovery Today 2010, 15, 812– 815 DOI: 10.1016/j.drudis.2010.08.010
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      When pharmaceutical companies publish large datasets: an abundance of riches or fool's gold?
      Ekins Sean; Williams Antony J
      Drug discovery today (2010), 15 (19-20), 812-5 ISSN:.
      The recent announcement that GlaxoSmithKline have released a huge tranche of whole-cell malaria screening data to the public domain, accompanied by a corresponding publication, raises some issues for consideration before this exemplar instance becomes a trend. We have examined the data from a high level, by studying the molecular properties, and consider the various alerts presently in use by major pharma companies. We not only acknowledge the potential value of such data but also raise the issue of the actual value of such datasets released into the public domain. We also suggest approaches that could enhance the value of such datasets to the community and theoretically offer an immediate benefit to the search for leads for other neglected diseases.
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      Boström, J.; Hogner, A.; Llinàs, A.; Wellner, E.; Plowright, A. T. Oxadiazoles in medicinal chemistry J. Med. Chem. 2012, 55, 1817– 1830 DOI: 10.1021/jm2013248
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      98
      Oxadiazoles in medicinal chemistry
      Bostrom Jonas; Hogner Anders; Llinas Antonio; Wellner Eric; Plowright Alleyn T
      Journal of medicinal chemistry (2012), 55 (5), 1817-30 ISSN:.
      Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.
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    99. 99
      OSM electronic laboratory notebook, pharmacophore modelling of OSM compounds: http://malaria.ourexperiment.org/pharmacophore_modelling_, accessed Dec 8, 2015.
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    100. 100
      Olesen, P. H. The use of bioisosteric groups in lead optimization Curr. Opin. Drug Discovery Dev. 2001, 4, 471– 478
      Google Scholar
      100
      The use of bioisosteric groups in lead optimization
      Olesen, Preben H.
      Current Opinion in Drug Discovery & Development (2001), 4 (4), 471-478CODEN: CODDFF; ISSN:1367-6733. (PharmaPress Ltd.)
      A review with refs. It is now half a century since Friedman introduced the term bioisosterism for the similar biol. activity of structurally related compds. Since then, the concept has been used extensively and successfully in the optimization of lead compds. in drug discovery. The no. of chem. lead compds. has expanded enormously in recent years due to the expression of an increasing no. of recombinant proteins, and the screening of these new protein targets against a large no. of compds. in high-throughput screens. For the fine-tuning of lead compds. to obtain candidates suitable for clin. trials, which is in most circumstances still a tedious process, the use of bioisosteric replacement can be of significant value. This is esp. the case in optimizing for selectivity for a specific target and in improving the pharmacokinetic properties of lead compds. The use of bioisosteres in lead optimization is illustrated by some recent examples from the literature.
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    101. 101
      Open Source Malaria Wiki, GSK Arylpyrrole Series: http://openwetware.org/wiki/OpenSourceMalaria:GSK_Arylpyrrole_Series, accessed Dec 8, 2015. (Snapshot available for download at The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/15389).
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    102. 102
      Berry, L. M.; Wollenberg, L.; Zhao, Z. Esterase activities in the blood, liver and intestine of several preclinical species and humans Drug Metab. Lett. 2009, 3, 70– 77 DOI: 10.2174/187231209788654081
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      102
      Esterase activities in the blood, liver and intestine of several preclinical species and humans
      Berry, Loren M.; Wollenberg, Lance; Zhao, Zhiyang
      Drug Metabolism Letters (2009), 3 (2), 70-77CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)
      Species and tissue differences in the activity of three major classes of esterases, carboxylesterase (CE), butyrylcholinesterase (BChE) and paraoxonase (PON), were studied. Substantial species differences in activity of these esterases were obsd. between the mouse, rat, dog monkey and human. Such species differences must be considered when using these preclin. species to optimize the pharmacokinetic properties of ester compds. intended for human use.
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    103. 103
      Danker, T.; Möller, C. Early identification of hERG liability in drug discovery programs by automated patch clamp Front. Pharmacol. 2014,  DOI: 10.3389/fphar.2014.00203
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      There is no corresponding record for this reference.
    104. 104
      Ruecker, A.; Mathias, D. K.; Straschil, U.; Churcher, T. S.; Dinglasan, R. R.; Leroy, D. A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs Antimicrob. Agents Chemother. 2014, 58, 7292– 7302 DOI: 10.1128/AAC.03666-14
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      104
      A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs
      Ruecker, A.; Mathias, D. K.; Straschil, U.; Churcher, T. S.; Dinglasan, R. R.; Leroy, D.; Sinden, R. E.; Delves, M. J.
      Antimicrobial Agents and Chemotherapy (2014), 58 (12), 7292-7302, 12 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Malaria elimination will require interventions that prevent parasite transmission from the human host to the mosquito. Exptl., this is usually detd. by the expensive and laborious Plasmodium falciparum std. membrane feeding assay (PfSMFA), which has limited utility for high-throughput drug screening. In response, we developed the P. falciparum dual gamete formation assay (PfDGFA), which faithfully simulates the initial stages of the PfSMFA in vitro. It utilizes a dual readout that individually and simultaneously reports on the functional viability of male and female mature stage V gametocytes. To validate, we screen the Medicines for Malaria Venture (MMV) Malaria Box library with the PfDGFA. Unique to this assay, we find compds. that target male gametocytes only and also compds. with reversible and irreversible activity. Most importantly, we show that compd. activity in the PfDGFA accurately predicts activity in PfSMFAs, which validates and supports its adoption into the transmission-stage screening pipeline.
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    105. 105
      Meister, S.; Plouffe, D. M.; Kuhen, K. L.; Bonamy, G. M. C.; Wu, T.; Barnes, S. W. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery Science 2011, 334, 1372– 1377 DOI: 10.1126/science.1211936
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      105
      Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery
      Meister, Stephan; Plouffe, David M.; Kuhen, Kelli L.; Bonamy, Ghislain M. C.; Wu, Tao; Barnes, S. Whitney; Bopp, Selina E.; Borboa, Rachel; Bright, A. Taylor; Che, Jianwei; Cohen, Steve; Dharia, Neekesh V.; Gagaring, Kerstin; Gettayacamin, Montip; Gordon, Perry; Groessl, Todd; Kato, Nobutaka; Lee, Marcus C. S.; McNamara, Case W.; Fidock, David A.; Nagle, Advait; Nam, Tae-gyu; Richmond, Wendy; Roland, Jason; Rottmann, Matthias; Zhou, Bin; Froissard, Patrick; Glynne, Richard J.; Mazier, Dominique; Sattabongkot, Jetsumon; Schultz, Peter G.; Tuntland, Tove; Walker, John R.; Zhou, Yingyao; Chatterjee, Arnab; Diagana, Thierry T.; Winzeler, Elizabeth A.
      Science (Washington, DC, United States) (2011), 334 (6061), 1372-1377CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 com. available compds. with previously demonstrated blood-stage activity (median inhibitory concn. < 1 micromolar) and identified chem. scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compds. active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chem. tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biol. of exo-erythrocytic forms.
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    106. 106
      Lee, A. Y.; St.Onge, R. P.; Proctor, M. J.; Wallace, I. M.; Nile, A. H.; Spagnuolo, P. A. Mapping the cellular response to small molecules using chemogenomic fitness signatures Science 2014, 344, 208– 211 DOI: 10.1126/science.1250217
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      106
      Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures
      Lee, Anna Y.; St. Onge, Robert P.; Proctor, Michael J.; Wallace, Iain M.; Nile, Aaron H.; Spagnuolo, Paul A.; Jitkova, Yulia; Gronda, Marcela; Wu, Yan; Kim, Moshe K.; Cheung-Ong, Kahlin; Torres, Nikko P.; Spear, Eric D.; Han, Mitchell K. L.; Schlecht, Ulrich; Suresh, Sundari; Duby, Geoffrey; Heisler, Lawrence E.; Surendra, Anuradha; Fung, Eula; Urbanus, Malene L.; Gebbia, Marinella; Lissina, Elena; Miranda, Molly; Chiang, Jennifer H.; Aparicio, Ana Maria; Zeghouf, Mahel; Davis, Ronald W.; Cherfils, Jacqueline; Boutry, Marc; Kaiser, Chris A.; Cummins, Carolyn L.; Trimble, William S.; Brown, Grant W.; Schimmer, Aaron D.; Bankaitis, Vytas A.; Nislow, Corey; Bader, Gary D.; Giaever, Guri
      Science (Washington, DC, United States) (2014), 344 (6180), 208-211CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small mols. affects biol. and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compd. in vivo to profile 3250 small mols. in a systematic and unbiased manner. We identified 317 compds. that specifically perturb the function of 121 genes and characterized the mechanism of specific compds. Global anal. revealed that the cellular response to small mols. is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chems., and biol. processes.
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    107. 107
      Subramanian, A.; Tamayo, P.; Mootha, V. K.; Mukherjee, S.; Ebert, B. L.; Gillette, M. A. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 15545– 15550 DOI: 10.1073/pnas.0506580102
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      107
      Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
      Subramanian, Aravind; Tamayo, Pablo; Mootha, Vamsi K.; Mukherjee, Sayan; Ebert, Benjamin L.; Gillette, Michael A.; Paulovich, Amanda; Pomeroy, Scott L.; Golub, Todd R.; Lander, Eric S.; Mesirov, Jill P.
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (43), 15545-15550CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Although genomewide RNA expression anal. has become a routine tool in biomedical research, extg. biol. insight from such information remains a major challenge. Here, we describe a powerful anal. method called Gene Set Enrichment Anal. (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, i.e., groups of genes that share common biol. function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene anal. finds little similarity between two independent studies of patients survival in lung cancer, GSEA reveals many biol. pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biol. defined gene sets.
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    108. 108
      Gupta, A. P.; Chin, W. H.; Zhu, L.; Mok, S.; Luah, Y.-H.; Lim, E.-H. Dynamic epigenetic regulation of gene expression during the life cycle of malaria parasite Plasmodium falciparum PLoS Pathog. 2013, 9, e1003170 DOI: 10.1371/journal.ppat.1003170
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      There is no corresponding record for this reference.
    109. 109
      Jiang, L.; Mu, J.; Zhang, Q.; Ni, T.; Srinivasan, P.; Rayavara, K. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum Nature 2013, 499, 223– 227 DOI: 10.1038/nature12361
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      109
      PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum
      Jiang, Lubin; Mu, Jianbing; Zhang, Qingfeng; Ni, Ting; Srinivasan, Prakash; Rayavara, Kempaiah; Yang, Wenjing; Turner, Louise; Lavstsen, Thomas; Theander, Thor G.; Peng, Weiqun; Wei, Guiying; Jing, Qingqing; Wakabayashi, Yoshiyuki; Bansal, Abhisheka; Luo, Yan; Ribeiro, Jose M. C.; Scherf, Artur; Aravind, L.; Zhu, Jun; Zhao, Keji; Miller, Louis H.
      Nature (London, United Kingdom) (2013), 499 (7457), 223-227CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a crit. virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection, the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here, the authors show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an ortholog of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.
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    110. 110
      Yu, L.; Lopez, A.; Anaflous, A.; El Bali, B.; Hamal, A.; Ericson, E. Chemical-genetic profiling of imidazo[1,2-a]pyridines and – pyrimidines reveals target pathways conserved between yeast and human cells PLoS Genet. 2008, 4, e1000284 DOI: 10.1371/journal.pgen.1000284
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    111. 111
      Sanz, L. M.; Crespo, B.; De-Cózar, C.; Ding, X. C.; Llergo, J. L.; Burrows, J. N. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action PLoS One 2012, 7, e30949 DOI: 10.1371/journal.pone.0030949
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      111
      P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action
      Sanz, Laura M.; Crespo, Benigno; De-Cozar, Cristina; Ding, Xavier C.; Llergo, Jose L.; Burrows, Jeremy N.; Garcia-Bustos, Jose F.; Gamo, Francisco-Javier
      PLoS One (2012), 7 (2), e30949CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately det. the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artifacts, as viability and metab. are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compds. on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodol. to measure in vitro the direct effect of antimalarial compds. over the parasite viability, which is based on limiting serial diln. of treated parasites and re-growth monitoring. This methodol. allows to precisely det. the killing rate of antimalarial compds., which can be quantified by the parasite redn. ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to det. compd. killing activities that might be otherwise missed by traditional, metab.-based techniques. The anal. of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compds. based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compds., which are crucially needed for the control and possibly the eradication of malaria.
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    112. 112
      Prathipati, P.; Ma, N. L.; Manjunatha, U. H.; Bender, A. Fishing the target of antitubercular compounds: in silico target deconvolution model development and validation J. Proteome Res. 2009, 8, 2788– 2798 DOI: 10.1021/pr8010843
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      112
      Fishing the Target of Antitubercular Compounds: In Silico Target Deconvolution Model Development and Validation
      Prathipati, Philip; Ma, Ngai Ling; Manjunatha, Ujjini H.; Bender, Andreas
      Journal of Proteome Research (2009), 8 (6), 2788-2798CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      An in silico target prediction protocol for antitubercular (antiTB) compds. has been proposed in this work. This protocol is the extension of a recently published 'domain fishing model' (DFM), validating its predicted targets on a set of 42 common antitubercular drugs. For the 23 antiTB compds. of the set which are directly linked to targets (see text for definition), the DFM exhibited a very good target prediction accuracy of 95%. For 19 compds. indirectly linked to targets also, a reasonable pathway/embedded pathway prediction accuracy of 84% was achieved. Since mostly eukaryotic ligand binding data was used for the DFM generation, the high target prediction accuracy for prokaryotes (which is an extrapolation from the training data) was unexpected and provides an addnl. proof of concept of the DFM. To est. the general applicability of the model, ligand-target coverage anal. was performed. Here, it was found that, although the DFM only modestly covers the entire TB proteome (32% of all proteins), it captures 70% of the proteome subset targeted by 42 common antiTB compds., which is in agreement with the good predictive ability of the DFM for the targets of the compds. chosen here. In a prospective validation, the model successfully predicted the targets of new antiTB compds., CBR-2092 and Amiclenomycin. Together, these findings suggest that in silico target prediction tools may be a useful supplement to existing, exptl. target deconvolution strategies.
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    113. 113
      Koutsoukas, A.; Simms, B.; Kirchmair, J.; Bond, P. J.; Whitmore, A. V.; Zimmer, S. From in silico target prediction to multi-target drug design: current databases, methods and applications J. Proteomics 2011, 74, 2554– 2574 DOI: 10.1016/j.jprot.2011.05.011
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      113
      From in silico target prediction to multi-target drug design: Current databases, methods and applications
      Koutsoukas, Alexios; Simms, Benjamin; Kirchmair, Johannes; Bond, Peter J.; Whitmore, Alan V.; Zimmer, Steven; Young, Malcolm P.; Jenkins, Jeremy L.; Glick, Meir; Glen, Robert C.; Bender, Andreas
      Journal of Proteomics (2011), 74 (12), 2554-2574CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
      A review. Given the tremendous growth of bioactivity databases, the use of computational tools to predict protein targets of small mols. has been gaining importance in recent years. Applications span a wide range, from the designed polypharmacol.' of compds. to mode-of-action anal. In this review, we firstly survey databases that can be used for ligand-based target prediction and which have grown tremendously in size in the past. We furthermore outline methods for target prediction that exist, both based on the knowledge of bioactivities from the ligand side and methods that can be applied in situations when a protein structure is known. Applications of successful in silico target identification attempts are discussed in detail, which were based partly or in whole on computational target predictions in the first instance. This includes the authors' own experience using target prediction tools, in this case considering phenotypic antibacterial screens and the anal. of high-throughput screening data. Finally, we will conclude with the prospective application of databases to not only predict, retrospectively, the protein targets of a small mol., but also how to design ligands with desired polypharmacol. in a prospective manner.
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    114. 114
      Martínez-Jiménez, F.; Papadatos, G.; Yang, L.; Wallace, I. M.; Kumar, V.; Pieper, U. Target prediction for an open access set of compounds active against Mycobacterium tuberculosis PLoS Comput. Biol. 2013, 9, e1003253 DOI: 10.1371/journal.pcbi.1003253
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      There is no corresponding record for this reference.
    115. 115
      Baldwin, J.; Farajallah, A. M.; Malmquist, N. A.; Rathod, P. K.; Phillips, M. A. Malarial dihydroorotate dehydrogenase: substrate and inhibitor specificity J. Biol. Chem. 2002, 277, 41827– 41834 DOI: 10.1074/jbc.M206854200
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      115
      Malarial Dihydroorotate Dehydrogenase
      Baldwin, Jeffrey; Farajallah, Azizeh M.; Malmquist, Nicholas A.; Rathod, Pradipsinh K.; Phillips, Margaret A.
      Journal of Biological Chemistry (2002), 277 (44), 41827-41834CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The malarial parasite relies on de novo pyrimidine biosynthesis to maintain its pyrimidine pools, and unlike the human host cell it is unable to scavenge preformed pyrimidines. Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidn. of dihydroorotate (DHO) to produce orotate, a key step in pyrimidine biosynthesis. The enzyme is located in the outer membrane of the mitochondria of the malarial parasite. To characterize the biochem. properties of the malarial enzyme, an N-terminally truncated version of P. falciparum DHODH has been expressed as a sol., active enzyme in E. coli. The recombinant enzyme binds 0.9 molar equivalents of the cofactor FMN and it has a pH max. of 8.0 (kcat 8 s-1, Km DHO (40-80 μM)). The substrate specificity of the ubiquinone cofactor (CoQn) that is required for the oxidn. of FMN in the second step of the reaction was also detd. The isoprenoid (n) length of CoQn was a determinant of reaction efficiency; CoQ4, CoQ6 and decylubiquinone (CoQD) were efficiently utilized in the reaction while cofactors lacking an isoprenoid tail (CoQ0 and vitamin K3) showed decreased catalytic efficiency, resulting from a 4 to 7-fold increase in K. Five potent inhibitors of mammalian DHODH (Redoxal, dichloroallyl lawsone or DCL, and three analogs of A77 1726) were tested as inhibitors of the malarial enzyme. All five compds. were poor inhibitors of the malarial enzyme, with IC50 values ranging from 0.1-1.0 mM. The IC50 values for inhibition of the malarial enzyme are 102-104-fold higher than the values reported for the mammalian enzyme, demonstrating that inhibitor binding to DHODH is species specific. These studies provide direct evidence that the malarial DHODH active site is different from the host enzyme, and that it is an attractive target for the development of new anti-malarial agents.
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    116. 116
      Spillman, N. J.; Allen, R. J. W.; McNamara, C. W.; Yeung, B. K. S.; Winzeler, E. A.; Diagana, T. T. Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials Cell Host Microbe 2013, 13, 227– 237 DOI: 10.1016/j.chom.2012.12.006
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      116
      Na+ Regulation in the Malaria Parasite Plasmodium falciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials
      Spillman, Natalie J.; Allen, Richard J. W.; McNamara, Case W.; Yeung, Bryan K. S.; Winzeler, Elizabeth A.; Diagana, Thierry T.; Kirk, Kiaran
      Cell Host & Microbe (2013), 13 (2), 227-237CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
      The malaria parasite Plasmodium falciparum establishes in the host erythrocyte plasma membrane new permeability pathways that mediate nutrient uptake into the infected cell. These pathways simultaneously allow Na+ influx, causing [Na+] in the infected erythrocyte cytosol to increase to high levels. The intraerythrocytic parasite itself maintains a low cytosolic [Na+] via unknown mechanisms. Here the authors present evidence that the intraerythrocytic parasite actively extrudes Na+ against an inward gradient via PfATP4, a parasite plasma membrane protein with sequence similarities to Na+-ATPases of lower eukaryotes. Mutations in PfATP4 confer resistance to a potent class of antimalarials, the spiroindolones. Consistent with this, the spiroindolones cause a profound disruption in parasite Na+ homeostasis, which is attenuated in parasites bearing resistance-conferring mutations in PfATP4. The mutant parasites also show some impairment of Na+ regulation. Taken together, the authors' results are consistent with PfATP4 being a Na+ efflux ATPase and a target of the spiroindolones.
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    117. 117
      White, N. J.; Pukrittayakamee, S.; Phyo, A. P.; Rueangweerayut, R.; Nosten, F.; Jittamala, P. Spiroindolone KAE609 for falciparum and vivax malaria N. Engl. J. Med. 2014, 371, 403– 410 DOI: 10.1056/NEJMoa1315860
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      117
      Spiroindolone KAE609 for falciparum and vivax malaria
      White, Nicholas J.; Pukrittayakamee, Sasithon; Phyo, Aung Pyae; Rueangweerayut, Ronnatrai; Nosten, Francois; Jittamala, Podjanee; Jeeyapant, Atthanee; Jain, Jay Prakash; Lefevre, Gilbert; Li, Ruobing; Magnusson, Baldur; Diagana, Thierry T.; Leong, F. Joel
      New England Journal of Medicine (2014), 371 (5), 403-410, 8 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      Background: KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analog with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum. Methods: We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria. The primary end point was the parasite clearance time. Results: The median parasite clearance time was 12 h in each cohort (interquartile range, 8 to 16 h in patients with P. vivax malaria and 10 to 16 h in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 h (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 h (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 h. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 h (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen. Conclusions: KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria.
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    118. 118
      Vaidya, A. B.; Morrisey, J. M.; Zhang, Z.; Das, S.; Daly, T. M.; Otto, T. D. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum Nat. Commun. 2014, 5, 5521 DOI: 10.1038/ncomms6521
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      118
      Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
      Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Inigo; Ferrer, Santiago; Belen Jimenez-Diaz, Maria; Martinez, Maria Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.
      Nature Communications (2014), 5 (), 5521CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      The quest for new antimalarial drugs, esp. those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chem. class of mols., pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compds. A pyrazoleamide compd. causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chem. class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chem. classes.
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    119. 119
      Jiménez-Díaz, M. B.; Ebert, D.; Salinas, Y.; Pradhan, A.; Lehane, A. M.; Myrand-Lapierre, M.-E. +)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E5455– E5462 DOI: 10.1073/pnas.1414221111
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      There is no corresponding record for this reference.
    120. 120
      Flannery, E. L.; McNamara, C. W.; Kim, S. W.; Kato, T. S.; Li, F.-W.; Teng, C. H. Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials ACS Chem. Biol. 2015, 10, 413– 420 DOI: 10.1021/cb500616x
      Google Scholar
      120
      Mutations in the P-Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials
      Flannery, Erika L.; McNamara, Case W.; Kim, Sang Wan; Kato, Tomoyo Sakata; Li, Fengwu; Teng, Christine H.; Gagaring, Kerstin; Manary, Micah J.; Barboa, Rachel; Meister, Stephan; Kuhen, Kelli; Vinetz, Joseph M.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.
      ACS Chemical Biology (2015), 10 (2), 413-420CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Aminopyrazoles are a new class of antimalarial compds. identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a crit. role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a crit. antimalarial target.
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    121. 121
      Lehane, A. M.; Ridgway, M. C.; Baker, E.; Kirk, K. Diverse chemotypes disrupt ion homeostasis in the malaria parasite Mol. Microbiol. 2014, 94, 327– 339 DOI: 10.1111/mmi.12765
      Google Scholar
      121
      Diverse chemotypes disrupt ion homeostasis in the malaria parasite
      Lehane, Adele M.; Ridgway, Melanie C.; Baker, Eileen; Kirk, Kiaran
      Molecular Microbiology (2014), 94 (2), 327-339CODEN: MOMIEE; ISSN:0950-382X. (Wiley-Blackwell)
      The antimalarial spiroindolones disrupt Plasmodium falciparum Na+ regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP4, a parasite plasma membrane P-type ATPase postulated to export Na+ and import H+ equiv. Here, we screened the 400 antiplasmodial compds. of the open access Malaria Box for their effects on parasite ion regulation. Twenty eight compds. affected parasite Na+ and pH regulation in a manner consistent with PfATP4 inhibition. Six of these, with chem. diverse structures, were selected for further anal. All 6 showed reduced antiplasmodial activity against spiroindolone-resistant parasites carrying mutations in pfatp4. We exposed parasites to incrementally increasing concns. of 2 of the 6 compds. and in both cases obtained resistant parasites with mutations in pfatp4. The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP4 may be a significant Achilles' heel for the parasite.
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    122. 122
      Open Source Malaria Wiki, Triazolopyrazine (TP) Series: http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series, accessed Dec 8, 2015. (Snapshot available for download at The University of Sydney eScholarship Repository at http://hdl.handle.net/2123/15389).
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      There is no corresponding record for this reference.
    123. 123
      van Voorhis, W. C.; Adams, J. H.; Adelfio, R.; Ahyong, V.; Akabas, M. H.; Alano, P. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond PLoS Pathog. 2016, 12, e1005763 DOI: 10.1371/journal.ppat.1005763
      Google Scholar
      123
      Open source drug discovery with the malaria box compound collection for neglected diseases and beyond
      Van Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Aleman Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jurgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Cassera, Maria Belen; Cheng, Ken Chih-Chien; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colon-Lopez, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D'Alessandro, Sarah; Dang, Na Le; Delves, Michael; De Risi, Joseph L.; Du, Alan Y.; Duffy, Sandra; El-Sayed, Shimaa Abd El-Salam; Ferdig, Michael T.; Fernandez Robledo, Jose A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Jensen, Amornrat Naranuntarat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinas, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Vera, Iset Medina; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Muller, Joachim; Muriana, Arantza; Hewitt, Stephen Nakazawa; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Rizk, Mohamed Abdo; Ruecker, Andrea; St. Onge, Robert; Ferreira, Rafaela Salgado; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Villela, Filipe Silva; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmuller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Vinh, Phat Voong; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.
      PLoS Pathogens (2016), 12 (7), e1005763/1-e1005763/23CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
      A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biol. is present in universities, whereas the focus of medicinal chem. is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could esp. be bridged through a scale-up of open sharing of phys. compds., which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compds. representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-anal. of the combined dataset. The combined biochem. and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compds. active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addn., many compds. demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicol., pharmacokinetic and metabolic properties were collected on all the compds., assisting in the selection of the most promising candidates for murine proof-of-concept expts. and medicinal chem. programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biol. assays involving human pathogens into drug discovery starting points, by providing open access to new families of mols., and emphasize how a small addnl. investment made to help acquire and distribute compds., and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chem. efforts.
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    124. 124
      Lowe, D. Company time for your own ideas, or not?In the Pipeline, 2016, http://blogs.sciencemag.org/pipeline/archives/2016/07/21/company-time-for-your-own-ideas-or-not, accessed July 25, 2016.
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