ACS Publications. Most Trusted. Most Cited. Most Read

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2002, 45, 8, 1712-1722
RETURN TO ISSUEPREVArticleNEXT

A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening

View Author Information
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, and Howard Hughes Medical Institute, W. M. Keck Institute for Cellular Visualization, Rosenstiel Basic Medical Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454
Cite this: J. Med. Chem. 2002, 45, 8, 1712–1722
Publication Date (Web):March 9, 2002
https://doi.org/10.1021/jm010533y
Copyright © 2002 American Chemical Society
Request reuse permissions

    Article Views

    9452

    Altmetric

    -

    Citations

    873
    LEARN ABOUT THESE METRICS
    Read OnlinePDF (256 KB)
    Get e-Alerts
    Supporting Info (1)»
    SUBJECTS:

    Abstract

    Abstract Image

    High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like:  they act noncompetitively, show little relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these “phony” hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including β-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical company. In addition to their original targets, 35 of these 45 compounds were shown to inhibit several unrelated model enzymes. These 35 screening hits included compounds, such as fullerenes, dyes, and quercetin, that have repeatedly shown activity against diverse targets. When tested against the model enzymes, the compounds showed time-dependent but reversible inhibition that was dramatically attenuated by albumin, guanidinium, or urea. Surprisingly, increasing the concentration of the model enzymes 10-fold largely eliminated inhibition, despite a 1000-fold excess of inhibitor; a well-behaved competitive inhibitor did not show this behavior. One model to explain these observations was that the active form of the promiscuous inhibitors was an aggregate of many individual molecules. To test this hypothesis, light scattering and electron microscopy experiments were performed. The nonspecific inhibitors were observed to form particles of 30−400 nm diameter by both techniques. In control experiments, a well-behaved competitive inhibitor and an inactive dye-like molecule were not observed to form aggregates. Consistent with the hypothesis that the aggregates are the inhibitory species, the particle size and IC50 values of the promiscuous inhibitors varied monotonically with ionic strength; a competitive inhibitor was unaffected by changes in ionic strength. Unexpectedly, aggregate formation appears to explain the activity of many nonspecific inhibitors and may account for the activity of many promiscuous screening hits. Molecules acting via this mechanism may be widespread in drug discovery screening databases. Recognition of these compounds may improve screening results in many areas of pharmaceutical interest.

    ‡

     Northwestern University.

    §

     Present address:  Dipartimento di Chimica, Università degli Studi di Modena, Via Campi 183, Modena, Italy.

    ⊥

     Brandeis University.

    *

     To whom correspondence should be addressed. Tel:  312-503-0081. Fax:  312-503-5349. E-mail:  [email protected].

    Supporting Information Available

    ARTICLE SECTIONS
    Jump To

    The structures of the compounds shown in Tables 1 and 6 (except tris(dicarboxymethylene)fullerene-C3) have been deposited in .sdf format. This material is available free of charge via the Internet at http://pubs.acs.org.

    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.

    Cited By

    This article is cited by 873 publications.

    1. Maude Petit, Jérémie Tessier, Célia Sahli, Andreea R. Schmitzer. Confronting the Threat: Designing Highly Effective bis-Benzimidazolium Agents to Overcome Biofilm Persistence and Antimicrobial Resistance. ACS Infectious Diseases 2023, 9 (11) , 2202-2214. https://doi.org/10.1021/acsinfecdis.3c00289
    2. James B. McAlpine, Daneel Ferreira, Neil E. Pauli, Stefan Gafner, Guido F. Pauli. The Ethics of Publishing Biomedical and Natural Products Research. Journal of Natural Products 2023, 86 (9) , 2228-2237. https://doi.org/10.1021/acs.jnatprod.3c00165
    3. John Ingersoll, Alexander A. Shcherbakov, Amit Vaish, Leszek Poppe. PEG: The Magic Bullet for Biophysical Analysis of Highly Aggregating Small Molecules in Aqueous Solutions. ACS Medicinal Chemistry Letters 2023, 14 (8) , 1063-1066. https://doi.org/10.1021/acsmedchemlett.3c00198
    4. Fatma Shahout, Marion Vanharen, Abdelaziz Saafane, James Gillard, Denis Girard, Steven R. LaPlante. Drug Self-Aggregation into Nano-Entities Has the Potential to Induce Immune Responses. Molecular Pharmaceutics 2023, 20 (8) , 4031-4040. https://doi.org/10.1021/acs.molpharmaceut.3c00196
    5. Isha Singh, Fengling Li, Elissa A. Fink, Irene Chau, Alice Li, Annía Rodriguez-Hernández, Isabella Glenn, Francisco J. Zapatero-Belinchón, M. Luis Rodriguez, Kanchan Devkota, Zhijie Deng, Kris White, Xiaobo Wan, Nataliya A. Tolmachova, Yurii S. Moroz, H. Ümit Kaniskan, Melanie Ott, Adolfo García-Sastre, Jian Jin, Danica Galonić Fujimori, John J. Irwin, Masoud Vedadi, Brian K. Shoichet. Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase. Journal of Medicinal Chemistry 2023, 66 (12) , 7785-7803. https://doi.org/10.1021/acs.jmedchem.2c02120
    6. Lucianna H. Santos, Thales Kronenberger, Renata G. Almeida, Elany B. Silva, Rafael E. O. Rocha, Joyce C. Oliveira, Luiza V. Barreto, Danielle Skinner, Pavla Fajtová, Miriam A. Giardini, Brendon Woodworth, Conner Bardine, André L. Lourenço, Charles S. Craik, Antti Poso, Larissa M. Podust, James H. McKerrow, Jair L. Siqueira-Neto, Anthony J. O’Donoghue, Eufrânio N. da Silva Júnior, Rafaela S. Ferreira. Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2. Journal of Chemical Information and Modeling 2022, 62 (24) , 6553-6573. https://doi.org/10.1021/acs.jcim.2c00693
    7. Ruihan Dong, Hongpeng Yang, Chengwei Ai, Guihua Duan, Jianxin Wang, Fei Guo. DeepBLI: A Transferable Multichannel Model for Detecting β-Lactamase-Inhibitor Interaction. Journal of Chemical Information and Modeling 2022, 62 (22) , 5830-5840. https://doi.org/10.1021/acs.jcim.2c01008
    8. Rabindranath Paul, Siddhartha Bera, Madhusmita Devi, Sandip Paul. Inhibition of Aβ16–22 Peptide Aggregation by Small Molecules and Their Permeation through POPC Lipid Bilayer: Insight from Molecular Dynamics Simulation Study. Journal of Chemical Information and Modeling 2022, 62 (21) , 5193-5207. https://doi.org/10.1021/acs.jcim.1c01366
    9. Andrés Sánchez-Ruiz, Gonzalo Colmenarejo. Systematic Analysis and Prediction of the Target Space of Bioactive Food Compounds: Filling the Chemobiological Gaps. Journal of Chemical Information and Modeling 2022, 62 (16) , 3734-3751. https://doi.org/10.1021/acs.jcim.2c00888
    10. Meihui Yi, Fengbin Wang, Weiyi Tan, Jer-Tsong Hsieh, Edward H. Egelman, Bing Xu. Enzyme Responsive Rigid-Rod Aromatics Target “Undruggable” Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment. Journal of the American Chemical Society 2022, 144 (29) , 13055-13059. https://doi.org/10.1021/jacs.2c05491
    11. Jinglin Fu, Kaitlyn Nguyen. Reduction of Promiscuous Peptides-Enzyme Inhibition and Aggregation by Negatively Charged Biopolymers. ACS Applied Bio Materials 2022, 5 (5) , 1839-1845. https://doi.org/10.1021/acsabm.1c01128
    12. Christophe Molina, Lilia Ait-Ouarab, Hervé Minoux. Isometric Stratified Ensembles: A Partial and Incremental Adaptive Applicability Domain and Consensus-Based Classification Strategy for Highly Imbalanced Data Sets with Application to Colloidal Aggregation. Journal of Chemical Information and Modeling 2022, 62 (8) , 1849-1862. https://doi.org/10.1021/acs.jcim.2c00293
    13. Pei W. Thomas, Eun Jeong Cho, Christopher R. Bethel, Thomas Smisek, Yeong-Chan Ahn, John M. Schroeder, Caitlyn A. Thomas, Kevin N. Dalby, Josh T. Beckham, Michael W. Crowder, Robert A. Bonomo, Walter Fast. Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM). ACS Infectious Diseases 2022, 8 (4) , 811-824. https://doi.org/10.1021/acsinfecdis.1c00577
    14. Christine A. Arbour, Barbara Imperiali. Backbone-Anchoring, Solid-Phase Synthesis Strategy To Access a Library of Peptidouridine-Containing Small Molecules. Organic Letters 2022, 24 (11) , 2170-2174. https://doi.org/10.1021/acs.orglett.2c00462
    15. Alexey Golovanov, Alexander Zhuravlev, Alejandro Cruz, Vladislav Aksenov, Rania Shafiullina, Kumar R. Kakularam, José M. Lluch, Hartmut Kuhn, Àngels González-Lafont, Igor Ivanov. N-Substituted 5-(1H-Indol-2-yl)-2-methoxyanilines Are Allosteric Inhibitors of the Linoleate Oxygenase Activity of Selected Mammalian ALOX15 Orthologs: Mechanism of Action. Journal of Medicinal Chemistry 2022, 65 (3) , 1979-1995. https://doi.org/10.1021/acs.jmedchem.1c01563
    16. Andrés Sánchez-Ruiz, Gonzalo Colmenarejo. Updated Prediction of Aggregators and Assay-Interfering Substructures in Food Compounds. Journal of Agricultural and Food Chemistry 2021, 69 (50) , 15184-15194. https://doi.org/10.1021/acs.jafc.1c05918
    17. Henry R. O’Donnell, Tia A. Tummino, Conner Bardine, Charles S. Craik, Brian K. Shoichet. Colloidal Aggregators in Biochemical SARS-CoV-2 Repurposing Screens. Journal of Medicinal Chemistry 2021, 64 (23) , 17530-17539. https://doi.org/10.1021/acs.jmedchem.1c01547
    18. Elany Barbosa da Silva, Débora A. Rocha, Isadora S. Fortes, Wenqian Yang, Ludovica Monti, Jair L. Siqueira-Neto, Conor R. Caffrey, James McKerrow, Saulo F. Andrade, Rafaela S. Ferreira. Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors. Journal of Medicinal Chemistry 2021, 64 (17) , 13054-13071. https://doi.org/10.1021/acs.jmedchem.1c01151
    19. Corentine M. C. Laurin, Joseph P. Bluck, Anthony K. N. Chan, Michelle Keller, Andrew Boczek, Amy R. Scorah, K. F. Larissa See, Laura E. Jennings, David S. Hewings, Fern Woodhouse, Jessica K. Reynolds, Matthias Schiedel, Philip G. Humphreys, Philip C. Biggin, Stuart J. Conway. Fragment-Based Identification of Ligands for Bromodomain-Containing Factor 3 of Trypanosoma cruzi. ACS Infectious Diseases 2021, 7 (8) , 2238-2249. https://doi.org/10.1021/acsinfecdis.0c00618
    20. Esther G. Kaye, Karishma Kailass, Oleg Sadovski, Andrew A. Beharry. A Green-Absorbing, Red-Fluorescent Phenalenone-Based Photosensitizer as a Theranostic Agent for Photodynamic Therapy. ACS Medicinal Chemistry Letters 2021, 12 (8) , 1295-1301. https://doi.org/10.1021/acsmedchemlett.1c00284
    21. Damir Bojadzic, Oscar Alcazar, Jinshui Chen, Sung-Ting Chuang, Jose M. Condor Capcha, Lina A. Shehadeh, Peter Buchwald. Small-Molecule Inhibitors of the Coronavirus Spike: ACE2 Protein–Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2. ACS Infectious Diseases 2021, 7 (6) , 1519-1534. https://doi.org/10.1021/acsinfecdis.1c00070
    22. Gangling Liao, Wenjuan Ye, Tyler Heitmann, Glen Ernst, Michael DePasquale, Laiyi Xu, Michael Wormald, Xin Hu, Marc Ferrer, Robert K. Harmel, Dorothea Fiedler, James Barrow, Huijun Wei. Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening. ACS Pharmacology & Translational Science 2021, 4 (2) , 780-789. https://doi.org/10.1021/acsptsci.0c00218
    23. Parnian Lak, Henry O’Donnell, Xuewen Du, Matthew P. Jacobson, Brian K. Shoichet. A Crowding Barrier to Protein Inhibition in Colloidal Aggregates. Journal of Medicinal Chemistry 2021, 64 (7) , 4109-4116. https://doi.org/10.1021/acs.jmedchem.0c02253
    24. Matthew J. Fuchter. On the Promise of Photopharmacology Using Photoswitches: A Medicinal Chemist’s Perspective. Journal of Medicinal Chemistry 2020, 63 (20) , 11436-11447. https://doi.org/10.1021/acs.jmedchem.0c00629
    25. Matthew D. Lloyd. High-Throughput Screening for the Discovery of Enzyme Inhibitors. Journal of Medicinal Chemistry 2020, 63 (19) , 10742-10772. https://doi.org/10.1021/acs.jmedchem.0c00523
    26. Simon Ng, Yu-Chi Juang, Arun Chandramohan, Hung Yi Kristal Kaan, Ahmad Sadruddin, Tsz Ying Yuen, Fernando J. Ferrer-Gago, Xue’Er Cheryl Lee, Xi Liew, Charles W. Johannes, Christopher J. Brown, Srinivasaraghavan Kannan, Pietro G. Aronica, Nils A. Berglund, Chandra S. Verma, Lijuan Liu, Alexander Stoeck, Tomi K. Sawyer, Anthony W. Partridge, David P. Lane. De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits. ACS Medicinal Chemistry Letters 2020, 11 (10) , 1993-2001. https://doi.org/10.1021/acsmedchemlett.0c00022
    27. Hongjian He, Weiyi Tan, Jiaqi Guo, Meihui Yi, Adrianna N. Shy, Bing Xu. Enzymatic Noncovalent Synthesis. Chemical Reviews 2020, 120 (18) , 9994-10078. https://doi.org/10.1021/acs.chemrev.0c00306
    28. Mohammad A. Ghattas, Sara Al Rawashdeh, Noor Atatreh, Richard A. Bryce. How Do Small Molecule Aggregates Inhibit Enzyme Activity? A Molecular Dynamics Study. Journal of Chemical Information and Modeling 2020, 60 (8) , 3901-3909. https://doi.org/10.1021/acs.jcim.0c00540
    29. Irem Kaya, Gonzalo Colmenarejo. Analysis of Nuisance Substructures and Aggregators in a Comprehensive Database of Food Chemical Compounds. Journal of Agricultural and Food Chemistry 2020, 68 (33) , 8812-8824. https://doi.org/10.1021/acs.jafc.0c02521
    30. Zi-Yi Yang, Jun-Hong He, Ai-Ping Lu, Ting-Jun Hou, Dong-Sheng Cao. Application of Negative Design To Design a More Desirable Virtual Screening Library. Journal of Medicinal Chemistry 2020, 63 (9) , 4411-4429. https://doi.org/10.1021/acs.jmedchem.9b01476
    31. Sudipto Debnath, Tuluma Das, Subrata Gayen, Tapas Ghosh, Dilip K. Maiti. Iodine-Catalyzed Functionalization of Primary Aliphatic Amines to Oxazoles, 1,4-Oxazines, and Oxazinones. ACS Omega 2019, 4 (23) , 20410-20422. https://doi.org/10.1021/acsomega.9b03501
    32. Hanbo Pan, Hongda Qiu, Ke Zhang, Panpan Zhang, Weida Liang, Mengxiang Yang, Chenye Mou, Miaoman Lin, Ming He, Xiao Xiao, Difan Zhang, Haixing Wang, Fufeng Liu, Yongmei Li, Haixiao Jin, Xiaojun Yan, Hongze Liang, Wei Cui. Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence. ACS Chemical Neuroscience 2019, 10 (11) , 4741-4756. https://doi.org/10.1021/acschemneuro.9b00503
    33. Hayarpi Torosyan, Brian K. Shoichet. Protein Stability Effects in Aggregate-Based Enzyme Inhibition. Journal of Medicinal Chemistry 2019, 62 (21) , 9593-9599. https://doi.org/10.1021/acs.jmedchem.9b01019
    34. Zi-Yi Yang, Zhi-Jiang Yang, Jie Dong, Liang-Liang Wang, Liu-Xia Zhang, Jun-Jie Ding, Xiao-Qin Ding, Ai-Ping Lu, Ting-Jun Hou, Dong-Sheng Cao. Structural Analysis and Identification of Colloidal Aggregators in Drug Discovery. Journal of Chemical Information and Modeling 2019, 59 (9) , 3714-3726. https://doi.org/10.1021/acs.jcim.9b00541
    35. Yann Ayotte, Victoria M. Marando, Louis Vaillancourt, Patricia Bouchard, Gregory Heffron, Paul W. Coote, Sacha T. Larda, Steven R. LaPlante. Exposing Small-Molecule Nanoentities by a Nuclear Magnetic Resonance Relaxation Assay. Journal of Medicinal Chemistry 2019, 62 (17) , 7885-7896. https://doi.org/10.1021/acs.jmedchem.9b00653
    36. Eric N. Donders, Ahil N. Ganesh, Hayarpi Torosyan, Parnian Lak, Brian K. Shoichet, Molly S. Shoichet. Triggered Release Enhances the Cytotoxicity of Stable Colloidal Drug Aggregates. ACS Chemical Biology 2019, 14 (7) , 1507-1514. https://doi.org/10.1021/acschembio.9b00247
    37. Peter J. Tonge. Quantifying the Interactions between Biomolecules: Guidelines for Assay Design and Data Analysis. ACS Infectious Diseases 2019, 5 (6) , 796-808. https://doi.org/10.1021/acsinfecdis.9b00012
    38. Keisuke Tomohara, Isao Adachi, Yoshikazu Horino, Hitoshi Kesamaru, Hitoshi Abe, Keitaro Suyama, Takeru Nose. DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors. ACS Medicinal Chemistry Letters 2019, 10 (6) , 923-928. https://doi.org/10.1021/acsmedchemlett.9b00093
    39. Stephen Boulton, Rajeevan Selvaratnam, Rashik Ahmed, Katherine Van, Xiaodong Cheng, Giuseppe Melacini. Mechanisms of Specific versus Nonspecific Interactions of Aggregation-Prone Inhibitors and Attenuators. Journal of Medicinal Chemistry 2019, 62 (10) , 5063-5079. https://doi.org/10.1021/acs.jmedchem.9b00258
    40. Thomas Blaschke, Filip Miljković, Jürgen Bajorath. Prediction of Different Classes of Promiscuous and Nonpromiscuous Compounds Using Machine Learning and Nearest Neighbor Analysis. ACS Omega 2019, 4 (4) , 6883-6890. https://doi.org/10.1021/acsomega.9b00492
    41. Ahil N. Ganesh, Ahmed Aman, Jennifer Logie, Ben L. Barthel, Peter Cogan, Rima Al-awar, Tad H. Koch, Brian K. Shoichet, Molly S. Shoichet. Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence. ACS Chemical Biology 2019, 14 (4) , 751-757. https://doi.org/10.1021/acschembio.9b00032
    42. Conrad Stork, Ya Chen, Martin Šícho, Johannes Kirchmair. Hit Dexter 2.0: Machine-Learning Models for the Prediction of Frequent Hitters. Journal of Chemical Information and Modeling 2019, 59 (3) , 1030-1043. https://doi.org/10.1021/acs.jcim.8b00677
    43. Pi-Chun Li, Jaebong Jang, Chih-Yun Hsia, Patrice V. Groomes, Wenlong Lian, Melissanne de Wispelaere, Jared D. Pitts, Jinhua Wang, Nicholas Kwiatkowski, Nathanael S. Gray, Priscilla L. Yang. Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo. ACS Infectious Diseases 2019, 5 (3) , 460-472. https://doi.org/10.1021/acsinfecdis.8b00322
    44. Erik Gilberg, Jürgen Bajorath. Recent Progress in Structure-Based Evaluation of Compound Promiscuity. ACS Omega 2019, 4 (2) , 2758-2765. https://doi.org/10.1021/acsomega.8b03639
    45. Erik Gilberg, Michael Gütschow, Jürgen Bajorath. Promiscuous Ligands from Experimentally Determined Structures, Binding Conformations, and Protein Family-Dependent Interaction Hotspots. ACS Omega 2019, 4 (1) , 1729-1737. https://doi.org/10.1021/acsomega.8b03481
    46. Eleni Kyriakou, Stefanie Schmidt, Garron T. Dodd, Katrin Pfuhlmann, Stephanie E. Simonds, Dominik Lenhart, Arie Geerlof, Sonja C. Schriever, Meri De Angelis, Karl-Werner Schramm, Oliver Plettenburg, Michael A. Cowley, Tony Tiganis, Matthias H. Tschöp, Paul T. Pfluger, Michael Sattler, Ana C. Messias. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. Journal of Medicinal Chemistry 2018, 61 (24) , 11144-11157. https://doi.org/10.1021/acs.jmedchem.8b01224
    47. Swarit Jasial, Erik Gilberg, Thomas Blaschke, Jürgen Bajorath. Machine Learning Distinguishes with High Accuracy between Pan-Assay Interference Compounds That Are Promiscuous or Represent Dark Chemical Matter. Journal of Medicinal Chemistry 2018, 61 (22) , 10255-10264. https://doi.org/10.1021/acs.jmedchem.8b01404
    48. C. Esposito, L. Wiedmer, A. Caflisch. In Silico Identification of JMJD3 Demethylase Inhibitors. Journal of Chemical Information and Modeling 2018, 58 (10) , 2151-2163. https://doi.org/10.1021/acs.jcim.8b00539
    49. Vishal B. Siramshetty, Robert Preissner, Bjoern-Oliver Gohlke. Exploring Activity Profiles of PAINS and Their Structural Context in Target–Ligand Complexes. Journal of Chemical Information and Modeling 2018, 58 (9) , 1847-1857. https://doi.org/10.1021/acs.jcim.8b00385
    50. Wenlong Lian, Jaebong Jang, Supanee Potisopon, Pi-Chun Li, Amal Rahmeh, Jinhua Wang, Nicholas P. Kwiatkowski, Nathanael S. Gray, Priscilla L. Yang. Discovery of Immunologically Inspired Small Molecules That Target the Viral Envelope Protein. ACS Infectious Diseases 2018, 4 (9) , 1395-1406. https://doi.org/10.1021/acsinfecdis.8b00127
    51. Matthew K. Matlock, Tyler B. Hughes, Jayme L. Dahlin, S. Joshua Swamidass. Modeling Small-Molecule Reactivity Identifies Promiscuous Bioactive Compounds. Journal of Chemical Information and Modeling 2018, 58 (8) , 1483-1500. https://doi.org/10.1021/acs.jcim.8b00104
    52. Lewis R. Vidler, Ian A. Watson, Brandon J. Margolis, David J. Cummins, Michael Brunavs. Investigating the Behavior of Published PAINS Alerts Using a Pharmaceutical Company Data Set. ACS Medicinal Chemistry Letters 2018, 9 (8) , 792-796. https://doi.org/10.1021/acsmedchemlett.8b00097
    53. Stephen Boulton, Rajeevan Selvaratnam, Jean-Paul Blondeau, Frank Lezoualc’h, Giuseppe Melacini. Mechanism of Selective Enzyme Inhibition through Uncompetitive Regulation of an Allosteric Agonist. Journal of the American Chemical Society 2018, 140 (30) , 9624-9637. https://doi.org/10.1021/jacs.8b05044
    54. John G. Quinn, Keith E. Pitts, Micah Steffek, Melinda M. Mulvihill. Determination of Affinity and Residence Time of Potent Drug-Target Complexes by Label-free Biosensing. Journal of Medicinal Chemistry 2018, 61 (12) , 5154-5161. https://doi.org/10.1021/acs.jmedchem.7b01829
    55. Brandon S. McCullough, Amy M. Barrios. Facile, Fluorogenic Assay for Protein Histidine Phosphatase Activity. Biochemistry 2018, 57 (18) , 2584-2589. https://doi.org/10.1021/acs.biochem.8b00278
    56. Martin Vogt, Swarit Jasial, Jürgen Bajorath. Extracting Compound Profiling Matrices from Screening Data. ACS Omega 2018, 3 (4) , 4706-4712. https://doi.org/10.1021/acsomega.8b00461
    57. H. Ümit Kaniskan, Michael L. Martini, and Jian Jin . Inhibitors of Protein Methyltransferases and Demethylases. Chemical Reviews 2018, 118 (3) , 989-1068. https://doi.org/10.1021/acs.chemrev.6b00801
    58. Erik Gilberg, Michael Gütschow, and Jürgen Bajorath . X-ray Structures of Target–Ligand Complexes Containing Compounds with Assay Interference Potential. Journal of Medicinal Chemistry 2018, 61 (3) , 1276-1284. https://doi.org/10.1021/acs.jmedchem.7b01780
    59. Erik Gilberg, Dagmar Stumpfe, and Jürgen Bajorath . X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design. ACS Omega 2018, 3 (1) , 106-111. https://doi.org/10.1021/acsomega.7b01849
    60. Christopher R. Vickery, B. McKay Wood, Heidi G. Morris, Richard Losick, and Suzanne Walker . Reconstitution of Staphylococcus aureus Lipoteichoic Acid Synthase Activity Identifies Congo Red as a Selective Inhibitor. Journal of the American Chemical Society 2018, 140 (3) , 876-879. https://doi.org/10.1021/jacs.7b11704
    61. Anamarija Zega . NMR Methods for Identification of False Positives in Biochemical Screens. Journal of Medicinal Chemistry 2017, 60 (23) , 9437-9447. https://doi.org/10.1021/acs.jmedchem.6b01520
    62. James M. Song, Arya Menon, Dylan C. Mitchell, Oleta T. Johnson, and Amanda L. Garner . High-Throughput Chemical Probing of Full-Length Protein–Protein Interactions. ACS Combinatorial Science 2017, 19 (12) , 763-769. https://doi.org/10.1021/acscombsci.7b00128
    63. Peter W. Kenny . Comment on The Ecstasy and Agony of Assay Interference Compounds. Journal of Chemical Information and Modeling 2017, 57 (11) , 2640-2645. https://doi.org/10.1021/acs.jcim.7b00313
    64. Michael R. Witten, Lisa Wissler, Melanie Snow, Stefan Geschwindner, Jon A. Read, Nicholas J. Brandon, Angus C. Nairn, Paul J. Lombroso, Helena Käck, and Jonathan A. Ellman . X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. Journal of Medicinal Chemistry 2017, 60 (22) , 9299-9319. https://doi.org/10.1021/acs.jmedchem.7b01292
    65. Jinshui Chen, Yun Song, Damir Bojadzic, Alejandro Tamayo-Garcia, Ana Marie Landin, Bonnie B. Blomberg, and Peter Buchwald . Small-Molecule Inhibitors of the CD40–CD40L Costimulatory Protein–Protein Interaction. Journal of Medicinal Chemistry 2017, 60 (21) , 8906-8922. https://doi.org/10.1021/acs.jmedchem.7b01154
    66. Tina Stark, Tobias Lieblein, Maximilian Pohland, Elisabeth Kalden, Petra Freund, René Zangl, Rekha Grewal, Mike Heilemann, Gunter P. Eckert, Nina Morgner, and Michael W. Göbel . Peptidomimetics That Inhibit and Partially Reverse the Aggregation of Aβ1–42. Biochemistry 2017, 56 (36) , 4840-4849. https://doi.org/10.1021/acs.biochem.7b00223
    67. Ahil N. Ganesh, Jennifer Logie, Christopher K. McLaughlin, Benjamin L. Barthel, Tad H. Koch, Brian K. Shoichet, and Molly S. Shoichet . Leveraging Colloidal Aggregation for Drug-Rich Nanoparticle Formulations. Molecular Pharmaceutics 2017, 14 (6) , 1852-1860. https://doi.org/10.1021/acs.molpharmaceut.6b01015
    68. Jonathan M. Blevitt, Michael D. Hack, Krystal L. Herman, Paul F. Jackson, Paul J. Krawczuk, Alec D. Lebsack, Annie X. Liu, Taraneh Mirzadegan, Marina I. Nelen, Aaron N. Patrick, Stefan Steinbacher, Marcos E. Milla, and Kevin J. Lumb . Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein–Protein Interaction. Journal of Medicinal Chemistry 2017, 60 (8) , 3511-3517. https://doi.org/10.1021/acs.jmedchem.6b01836
    69. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. ACS Infectious Diseases 2017, 3 (4) , 259-262. https://doi.org/10.1021/acsinfecdis.7b00023
    70. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. ACS Medicinal Chemistry Letters 2017, 8 (4) , 379-382. https://doi.org/10.1021/acsmedchemlett.7b00056
    71. Ahil N. Ganesh, Christopher K. McLaughlin, Da Duan, Brian K. Shoichet, and Molly S. Shoichet . A New Spin on Antibody–Drug Conjugates: Trastuzumab-Fulvestrant Colloidal Drug Aggregates Target HER2-Positive Cells. ACS Applied Materials & Interfaces 2017, 9 (14) , 12195-12202. https://doi.org/10.1021/acsami.6b15987
    72. Weilin Zhang, Jianfeng Pei, and Luhua Lai . Computational Multitarget Drug Design. Journal of Chemical Information and Modeling 2017, 57 (3) , 403-412. https://doi.org/10.1021/acs.jcim.6b00491
    73. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. Journal of Chemical Information and Modeling 2017, 57 (3) , 387-390. https://doi.org/10.1021/acs.jcim.7b00105
    74. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. Journal of Medicinal Chemistry 2017, 60 (6) , 2165-2168. https://doi.org/10.1021/acs.jmedchem.7b00229
    75. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. ACS Central Science 2017, 3 (3) , 143-147. https://doi.org/10.1021/acscentsci.7b00069
    76. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. ACS Chemical Biology 2017, 12 (3) , 575-578. https://doi.org/10.1021/acschembio.7b00119
    77. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. ACS Chemical Neuroscience 2017, 8 (3) , 420-423. https://doi.org/10.1021/acschemneuro.7b00064
    78. Courtney Aldrich (Editor-in-Chief) , Carolyn Bertozzi (Editor-in-Chief) , Gunda I. Georg (Editor-in-Chief) , Laura Kiessling (Editor-in-Chief) , Craig Lindsley (Editor-in-Chief) , Dennis Liotta (Editor-in-Chief) , Kenneth M. Merz, Jr. (Editor-in-Chief) , Alanna Schepartz (Editor-in-Chief) , Shaomeng Wang (Editor-in-Chief) . The Ecstasy and Agony of Assay Interference Compounds. Biochemistry 2017, 56 (10) , 1363-1366. https://doi.org/10.1021/acs.biochem.7b00110
    79. Muhammad Waqas, Woo-jin Jeong, Young-Joo Lee, Dae-Hwan Kim, Chongsuk Ryou, and Yong-beom Lim . pH-Dependent In-Cell Self-Assembly of Peptide Inhibitors Increases the Anti-Prion Activity While Decreasing the Cytotoxicity. Biomacromolecules 2017, 18 (3) , 943-950. https://doi.org/10.1021/acs.biomac.6b01816
    80. Ramkrishna Adhikary, Jörg Zimmermann, and Floyd E. Romesberg . Transparent Window Vibrational Probes for the Characterization of Proteins With High Structural and Temporal Resolution. Chemical Reviews 2017, 117 (3) , 1927-1969. https://doi.org/10.1021/acs.chemrev.6b00625
    81. Da Duan, Hayarpi Torosyan, Daniel Elnatan, Christopher K. McLaughlin, Jennifer Logie, Molly S. Shoichet, David A. Agard, and Brian K. Shoichet . Internal Structure and Preferential Protein Binding of Colloidal Aggregates. ACS Chemical Biology 2017, 12 (1) , 282-290. https://doi.org/10.1021/acschembio.6b00791
    82. Erik Gilberg, Swarit Jasial, Dagmar Stumpfe, Dilyana Dimova, and Jürgen Bajorath . Highly Promiscuous Small Molecules from Biological Screening Assays Include Many Pan-Assay Interference Compounds but Also Candidates for Polypharmacology. Journal of Medicinal Chemistry 2016, 59 (22) , 10285-10290. https://doi.org/10.1021/acs.jmedchem.6b01314
    83. Kévin Cottet, Bin Xu, Pascale Coric, Serge Bouaziz, Sylvie Michel, Michel Vidal, Marie-Christine Lallemand, and Sylvain Broussy . Guttiferone A Aggregates Modulate Silent Information Regulator 1 (SIRT1) Activity. Journal of Medicinal Chemistry 2016, 59 (20) , 9560-9566. https://doi.org/10.1021/acs.jmedchem.6b01182
    84. Bhanita Sharma and Sandip Paul . Action of Caffeine as an Amyloid Inhibitor in the Aggregation of Aβ16–22 Peptides. The Journal of Physical Chemistry B 2016, 120 (34) , 9019-9033. https://doi.org/10.1021/acs.jpcb.6b03892
    85. Valerie J. Winton, Claudia Aldrich, and Laura L. Kiessling . Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes. ACS Infectious Diseases 2016, 2 (8) , 538-543. https://doi.org/10.1021/acsinfecdis.6b00021
    86. Ariel A. Valiente-Gabioud, Marco C. Miotto, María E. Chesta, Verónica Lombardo, Andres Binolfi, and Claudio O. Fernández . Phthalocyanines as Molecular Scaffolds to Block Disease-Associated Protein Aggregation. Accounts of Chemical Research 2016, 49 (5) , 801-808. https://doi.org/10.1021/acs.accounts.5b00507
    87. John J. Irwin and Brian K. Shoichet . Docking Screens for Novel Ligands Conferring New Biology. Journal of Medicinal Chemistry 2016, 59 (9) , 4103-4120. https://doi.org/10.1021/acs.jmedchem.5b02008
    88. Christopher K. McLaughlin, Da Duan, Ahil N. Ganesh, Hayarpi Torosyan, Brian K. Shoichet, and Molly S. Shoichet . Stable Colloidal Drug Aggregates Catch and Release Active Enzymes. ACS Chemical Biology 2016, 11 (4) , 992-1000. https://doi.org/10.1021/acschembio.5b00806
    89. Elke Prade, Christian Barucker, Riddhiman Sarkar, Gerhard Althoff-Ospelt, Juan Miguel Lopez del Amo, Shireen Hossain, Yifei Zhong, Gerd Multhaup, and Bernd Reif . Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer’s Disease Amyloid-β Peptide Which Exhibit Reduced Neurotoxicity. Biochemistry 2016, 55 (12) , 1839-1849. https://doi.org/10.1021/acs.biochem.5b01272
    90. Jonathan Bisson, James B. McAlpine, J. Brent Friesen, Shao-Nong Chen, James Graham, and Guido F. Pauli . Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?. Journal of Medicinal Chemistry 2016, 59 (5) , 1671-1690. https://doi.org/10.1021/acs.jmedchem.5b01009
    91. Alex M. Clark, Krishna Dole, and Sean Ekins . Open Source Bayesian Models. 3. Composite Models for Prediction of Binned Responses. Journal of Chemical Information and Modeling 2016, 56 (2) , 275-285. https://doi.org/10.1021/acs.jcim.5b00555
    92. Gerald Maggiora Vijay Gokhale . Non-Specificity of Drug-Target Interactions – Consequences for Drug Discovery. 2016, 91-142. https://doi.org/10.1021/bk-2016-1222.ch007
    93. Xuewen Du, Jie Zhou, Junfeng Shi, and Bing Xu . Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials. Chemical Reviews 2015, 115 (24) , 13165-13307. https://doi.org/10.1021/acs.chemrev.5b00299
    94. Tianlu Wang, Tingting Hong, Yue Huang, Haomiao Su, Fan Wu, Yi Chen, Lai Wei, Wei Huang, Xiaoluan Hua, Yu Xia, Jinglei Xu, Jianhua Gan, Bifeng Yuan, Yuqi Feng, Xiaolian Zhang, Cai-Guang Yang, and Xiang Zhou . Fluorescein Derivatives as Bifunctional Molecules for the Simultaneous Inhibiting and Labeling of FTO Protein. Journal of the American Chemical Society 2015, 137 (43) , 13736-13739. https://doi.org/10.1021/jacs.5b06690
    95. Virginia A. Kincaid, Nir London, Kittikhun Wangkanont, Darryl A. Wesener, Sarah A. Marcus, Annie Héroux, Lyudmila Nedyalkova, Adel M. Talaat, Katrina T. Forest, Brian K. Shoichet, and Laura L. Kiessling . Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents. ACS Chemical Biology 2015, 10 (10) , 2209-2218. https://doi.org/10.1021/acschembio.5b00370
    96. Junfeng Shi, Xuewen Du, Dan Yuan, Richard Haburcak, Ning Zhou, and Bing Xu . Supramolecular Detoxification of Neurotoxic Nanofibrils of Small Molecules via Morphological Switch. Bioconjugate Chemistry 2015, 26 (9) , 1879-1883. https://doi.org/10.1021/acs.bioconjchem.5b00356
    97. John J. Irwin, Da Duan, Hayarpi Torosyan, Allison K. Doak, Kristin T. Ziebart, Teague Sterling, Gurgen Tumanian, and Brian K. Shoichet . An Aggregation Advisor for Ligand Discovery. Journal of Medicinal Chemistry 2015, 58 (17) , 7076-7087. https://doi.org/10.1021/acs.jmedchem.5b01105
    98. Atanu Biswas, Prashant Kurkute, Suraiya Saleem, Batakrishna Jana, Saswat Mohapatra, Prasenjit Mondal, Anindyasundar Adak, Subhajit Ghosh, Abhijit Saha, Debmalya Bhunia, Subhash Chandra Biswas, and Surajit Ghosh . Novel Hexapeptide Interacts with Tubulin and Microtubules, Inhibits Aβ Fibrillation, and Shows Significant Neuroprotection. ACS Chemical Neuroscience 2015, 6 (8) , 1309-1316. https://doi.org/10.1021/acschemneuro.5b00149
    99. Dan Yuan, Junfeng Shi, Xuewen Du, Ning Zhou, and Bing Xu . Supramolecular Glycosylation Accelerates Proteolytic Degradation of Peptide Nanofibrils. Journal of the American Chemical Society 2015, 137 (32) , 10092-10095. https://doi.org/10.1021/jacs.5b05888
    100. Anura S. Indulkar, Karl J. Box, Robert Taylor, Rebeca Ruiz, and Lynne S. Taylor . pH-Dependent Liquid–Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs. Molecular Pharmaceutics 2015, 12 (7) , 2365-2377. https://doi.org/10.1021/acs.molpharmaceut.5b00056
    Load more citations
    Download PDF

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect