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Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays
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  • Bongkochawan Pakamwong
    Bongkochawan Pakamwong
    Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
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    Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
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    Naruedon Phusi
    Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
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    Somjintana Taveepanich
    Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
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    Kampanart Chayajarus
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    Auradee Punkvang
    Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand
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    Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
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    Jidapa Sangswan
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    Khomson Suttisintong
    National Nanotechnology Center, NSTDA, 111 Thailand Science Park, Klong Luang, Pathum Thani 12120, Thailand
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    Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
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    Prasat Kittakoop
    Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
    Program in Chemical Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand
    Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10210, Thailand
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    Pitak Santanirand
    Division of Clinical Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
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    Jiraporn Leanpolchareanchai
    Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
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    James Spencer
    School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, U.K.
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    Adrian J. Mulholland
    Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
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  • Pornpan Pungpo*
    Pornpan Pungpo
    Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
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Journal of Chemical Information and Modeling

Cite this: J. Chem. Inf. Model. 2024, 64, 15, 5991–6002
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https://doi.org/10.1021/acs.jcim.4c00511
Published July 12, 2024

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Abstract

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Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14. Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC50 values of compounds 8, 11, and 14 (0.26, 0.56, and 0.08 μM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 μg/mL, respectively, superior to novobiocin (MIC > 100.0 μg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8, 11, and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.

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1. Introduction

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Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis, is the leading global cause of death from a single infectious agent, ranking above HIV/AIDS. In 2022, the number of people dying from TB increased to a total of 1.3 million, and an estimated 10.6 million people worldwide fell ill with TB. The global impact of TB disease, together with the increasing incidence of multidrug-resistant (MDR) strains, has led the World Health Organization to place M. tuberculosis in its highest (critical) category of bacterial pathogens against which new antibacterials must be developed. (1)
Mycobacterium tuberculosis DNA gyrase, comprising DNA gyrase A (GyrA) and DNA gyrase B (GyrB), regulates DNA topology by introducing negative supercoils into DNA using ATP as a cofactor. (2,3) GyrA catalyzes the breakage and religation of bound DNA (the gate or G-segment), whereas GyrB both captures a second DNA segment (the translocated or T-segment) and is responsible for the hydrolysis of ATP. (4) Based on these catalytic functions of DNA Gyrase, two binding sites, the DNA cleavage-ligation active site and the ATP binding site, have been validated as target binding sites for anti-tuberculosis agents. Fluoroquinolone (FQ) antibacterials, such as ciprofloxacin, ofloxacin, levofloxacin, and moxifloxacin, are DNA gyrase inhibitors binding to the cleavage-ligation active site and are extensively used antibiotics, serving as second-line agents in the treatment of infections caused by multidrug-resistant (MDR) tuberculosis strains. (5−10) However, mutations close to the DNA binding site of DNA gyrase reduce the potency of fluoroquinolones. (11−16)
The development of fluoroquinolone resistance has prompted the discovery of novel compounds that interfere with an alternative catalytic function of DNA gyrase, namely the ATPase activity catalyzed by the GyrB subunit. Inhibition of ATPase activity by these compounds involves noncovalent binding to the ATP binding site. Derivatives of quinoline, (17−19) aminopiperidine, (20) thiazole, (21−23) pyrrolamide, (24) benzofurans, (25,26) benzo[d]isothiazole, (25) benzimidazole, (27) phenylthiophene, (28,29) and pyrimido[4,5-b]indol-8-amine (30,31) scaffolds have all been identified as inhibitors of the ATPase activity of M. tuberculosis DNA gyrase. Furthermore, in our previous work benzoindole and indole derivatives (32,33) have been identified as novel M. tuberculosis DNA gyrase ATPase inhibitors using virtual screening, and subsequently validated in biological assays. However, most of these compounds exhibited limited efficacy against the growth of M. tuberculosis, with minimal inhibitory concentration (MIC) values exceeding 100 μg/mL. The exceptions were the two indole derivatives G24 and G26, which both showed MIC values of 12.5 μg/mL, i.e., significantly more active against M. tuberculosis than the known DNA gyrase inhibitor novobiocin (34) (MIC > 100 μg/mL) which is to date the only DNA gyrase ATPase inhibitor to have reached the clinic. (35) The cytotoxicity of indole derivative G24 is lower than that of indole derivative G26, as evidenced by a maximum non-cytotoxic concentration of G24 (25 μg/mL) 15-fold higher than for G26 (1.63 μg/mL).
Based on these data, along with encouraging cytotoxicity results (see below) the indole derivative G24 was considered suitable for optimization to develop more potent DNA gyrase inhibitors. However, optimization of a lead compound, involving selection of structural modifications followed by synthesis and biological assay, can be both time-consuming and budget-intensive. In contrast, virtual screening can be a cost-effective and time-saving technique for discovery of new compounds. (36−38) This approach has been successfully used to identify multiple candidate anti-tuberculosis agents including inhibitors of PknB, PknG, DprE1, MurB, RpfB, DXPS, PimA, and CtpF. (39−46) Based on these promising previous findings, the indole derivative G24 was utilized as the starting template for structural similarity searches, constituting the initial step in the virtual screening approach used in the present work. These identified multiple candidate ATPase inhibitors from the compound library of the Specs database (www.specs.net). Biological evaluation, including determination of minimum inhibitory concentration (MIC) for M. tuberculosis growth inhibition, and half-maximal inhibitory concentration (IC50) for GyrB ATPase activity in vitro, showed that five of these compounds are significantly more effective for inhibition of M. tuberculosis growth and DNA gyrase ATPase activity than the initial indole derivative G24. These findings demonstrate the ability of virtual screening to identify novel inhibitors of M. tuberculosis DNA gyrase ATPase activity that inhibit growth of M. tuberculosis.

2. Materials and Methods

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2.1. Virtual Screening Approach

Previously, our efforts aimed to identify inhibitors of the M. tuberculosis DNA gyrase ATPase, employing virtual screening techniques. However, due to the absence of available X-ray crystal structures of M. tuberculosis GyrB complexed with inhibitors, ligand-based virtual screening was limited. In one of our publications, we detailed the use of ligand-based virtual screening with bioisosteric designed compounds as templates, followed by structure-based virtual screening and biological assays. This approach resulted in a substantial percentage (78%) of hits yielding leads capable of inhibiting ATPase activity (Table S1), but none exhibited a minimal inhibitory concentration (MIC) against the growth of M. tuberculosis H37Ra. (32) This outcome may be attributed to the fact that the designed template used in this study was not evaluated for inhibiting the growth of M. tuberculosis. Consequently, in another publication, we exclusively employed structure-based virtual screening, which marginally increased the percentage (7%) of hits to leads active against both the growth of M. tuberculosis and ATPase activity (Table S1). (33) One of these identified leads, indole derivative G24, served as the template for ligand-based virtual screening in this study. Utilizing this compound as the template, all small molecules (492,534 compounds) in the Specs database (http://www.specs.net) were initially filtered by structural similarity search carried out on http://www.specs.net with a threshold of 60 percent (Figure 1). Filtered compounds that complied with Lipinski’s rule of five, and were not excluded by subsequent screening to exclude pan-assay interference compounds (PAINS) evaluated on http://www.swissadme.ch/index.php, (47) were chosen for further investigation. Biological tests of these compounds against the growth of M. tuberculosis were subsequently checked on the PubChem web interface, an open chemistry database providing chemical information from authoritative sources (https://pubchem.ncbi.nlm.nih.gov/). (48) Compounds displaying both active and inactive responses against M. tuberculosis growth in PubChem were excluded, as their biological activities have already been reported in other work. Compounds present in PubChem without recorded biological evaluation against M. tuberculosis growth were subjected to structural clustering using ChemMine tools. (49) Those resembling the inactive compounds within PubChem were removed, whereas the remaining compounds were considered as potential hits (Figure 2).

Figure 1

Figure 1. Virtual screening workflow for discovery of M. tuberculosis DNA gyrase inhibitors.

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Figure 2

Figure 2. New hit compounds identified in this work. Structures of hit compounds (1–14), G24, and novobiocin together with Specs code, MIC against M. tuberculosis H37Ra, and IC50 for inhibition of M. tuberculosis DNA gyrase ATPase activity. ND indicates not determined.

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2.2. Antimycobacterial Assay

The determination of the minimum inhibitory concentration (MIC) for the hit compounds against the growth of M. tuberculosis H37Ra was conducted through a microplate Alamar blue assay (MABA), as described in our previous work. (33) Hit compounds were purchased from the vendor (www.specs.net), dissolved in DMSO (Sigma-Aldrich) and then subjected to serial two-fold dilution, resulting in final concentrations ranging from 0.1 to 100 μg/mL, maintaining a constant DMSO concentration of 0.156% v/v. A mycobacterial suspension was prepared in a solution of 0.04% Tween 80, which was subsequently diluted with sterile distilled water to attain turbidity equivalent to a McFarland standard of no. 1. Following this, the suspension was further diluted at a 1:50 ratio with Middlebrook 7H9 media containing 0.2% v/v glycerol and 1.0 g/L casitone (7H9GC). Subsequently, 100 μL of this diluted suspension was added to each well of the microplate used for the assay. After an incubation period of approximately 7 days at 37 °C, a mixture of 12.5 μL of 20% Tween 80 and 20 μL of Alamar blue (SeroTec Ltd., Oxford, UK) was added to all wells. The growth of the microorganisms was assessed after an additional pre-incubation period of 16–24 h at 37 °C, during which time a visible color shift from blue to pink indicated positive growth. The MIC is defined as the lowest concentration at which the color change was prevented. Novobiocin (Sigma-Aldrich) was used as a positive control.

2.3. Overexpression and Purification of M. tuberculosis GyrA and GyrB

The overexpression, expression, and purification of M. tuberculosis DNA GyrA and GyrB were detailed in our previous work. (33) In brief, PCR-amplified fragments corresponding to the M. tuberculosis GyrA and GyrB subunits were individually cloned into the NdeI/XhoI restriction sites of the pET21a(+) and pET28a(+) vectors (Novagen), resulting in plasmids encoding GyrA with a C-terminal hexa-histidine tag and GyrB with an N-terminal hexa-histidine tag. Subsequently, these plasmids were transformed into E. coli BL21(DE3)pLysS (50) (Novagen) using the heat-shock method to express recombinant proteins. Cultures of E. coli BL21(DE3) pLysS were grown in LB medium, supplemented with ampicillin for GyrA and kanamycin for GyrB. Subsequently, 0.2 mM isopropyl-β-D-thiogalactopyranoside (IPTG) was used to induce expression. Protein purification was performed using Ni-NTA beads manually packed into a 2.5 cm diameter polypropylene gravity-flow column (Expedeon). The purity of these proteins was analyzed by 10% Sodium Dodecyl Sulfate polyacrylamide gel electrophoresis (SDS-PAGE). (51)

2.4. Inhibition (IC50) Assays of M. tuberculosis DNA Gyrase ATPase Activity

Inhibition of M. tuberculosis DNA gyrase holoenzyme was measured by monitoring ATPase activity using the coupled pyruvate kinase/lactate dehydrogenase assay, consistent with our aim of identifying inhibitors of GyrB ATPase activity as opposed to agents acting upon gyrase by other mechanisms. Half-maximal inhibitory concentration (IC50) values for inhibition of M. tuberculosis DNA gyrase ATPase activity were evaluated for hit compounds as described in our previous work. (33) Novobiocin (Sigma-Aldrich) was used as a positive control. IC50 determinations were carried out using data collected in triplicate, involving at least 11 inhibitor concentrations obtained from a serial 2-fold dilution, and values calculated from logIC50 obtained by fitting the dependence of % inhibition (obtained by normalizing data) on the log of inhibitor concentration using nonlinear regression in GraphPad Prism 8 (GraphPad Inc.).

2.5. In Vitro Cytotoxicity Study

Caco-2 cells (ATCC no. HTB-37) were used for cytotoxicity testing of selected compounds as described in our previous work. (32) Cell viability of tested compounds on Caco-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) following a modified assay procedure. (52) Absorbance was measured at 590 nm using a microplate reader (Infinite M200 PRO, Tecan Group Ltd., Switzerland). The experiment was performed in triplicate and compound concentrations at which cells retained a viability of more than 80% were considered as nontoxic to cells. (53)

2.6. Molecular Docking Calculations

Molecular docking calculations were used to generate the initial complexes between the GyrB subunit of M. tuberculosis and inhibitors. These complexes were then employed in molecular dynamics (MD) simulations. The docking calculations were conducted using the Glide program (54−56) in extra precision (XP) mode and were executed on a DELL Intel Core i5-7500 computer, as detailed in our previous work. (33) Four X-ray crystal structures of the ATPase domain of the M. tuberculosis GyrB subunit are available: one in the apo form (PDB code 6GAV) (57) and three in the holo form complexed with AMPPCP (PDB code 3ZM7) (58) and AMPPNP (PDB codes 3ZKD and 6GAU), (57,58) functioning as nonhydrolyzable ATP analogues. However, X-ray crystal structures of the M. tuberculosis GyrB subunit complexed with other inhibitors are not currently available. In contrast, structures of GyrB fragments complexed with inhibitors (PDB codes 4BAE, 6Y8O, and 4B6C) (24,31,59) are available for M. smegmatis, another species of mycobacterium that does not cause tuberculosis. Due to the current unavailability of any structure of the M. tuberculosis GyrB subunit bound to an inhibitor, other than nonhydrolyzable ATP analogues, we utilized the GyrB 47 kDa ATPase domain structure, complexed with inhibitor G24 and obtained from our previously described MD simulations, (33) for the docking calculations in this study. The Protein Preparation Wizard Workflow and LigPrep module integrated within the Maestro program (60,61) were employed for receptor and small molecule preparation, respectively. The initial 2D coordinates of all small molecules downloaded from the Specs database were generated as 3D structures (mol2 format) using the LigPrep module and subsequently used for molecular docking calculations. The docking grid box was assigned using the default protocol and centered upon inhibitor G24.

2.7. Molecular Dynamic Simulations

The initial inhibitor/enzyme complex structures generated from molecular docking calculations were used for MD simulations using AMBER20 software (62) on high performance computing GPU hardware as described in our previous work. (33) The Amber ff14SB force field was used for GyrB, and the general Amber force field (GAFF) (63) and restrained electrostatic potential (RESP) partial charges (64−66) were used for inhibitors. The initial complex structure was solvated with TIP3P water molecules (67) in a cubic box extending 10 Å from the solute species. Na+ ions were added to neutralize the system. Energy minimization was performed using a steepest descent algorithm followed by a conjugate gradient algorithm. This was followed by 70 ps of position-restrained dynamics simulation with a restraining weight of 2 kcal/mol Å2 at 300 K under an isobaric condition. Finally, three replicate 200 ns MD simulations were performed with no restraints using the same conditions. The cpptraj module (68) in AMBER20 was employed for the root-mean-square deviation (RMSD) calculations, for analysis of hydrogen bonding and clustering of the snapshots collected from the equilibrium state of each system.

2.8. Binding Free Energy Calculation

Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics Generalized Born surface area (MM/GBSA) methods (69) as described in our previous work (33) were used to estimate the binding free energies (ΔGPBSA and ΔGGBSA, respectively) of the receptor–ligand complexes obtained from MD simulations. Snapshots extracted every 40 ps over the equilibrium state of the MD simulation of each receptor–ligand complex were used to calculate ΔGPBSA and ΔGGBSA. The entropy contribution was excluded from the calculations of ΔGPBSA and ΔGGBSA, due to possibility of introduction of additional errors. (70,71)

2.9. Pairwise Energy Decomposition

Pairwise energy decomposition was employed to calculate the interaction energies between pairs of M. tuberculosis GyrB residues and inhibitors in the enzyme–inhibitor complexes. This approach was utilized to quantitatively analyze the contribution of individual residues in the M. tuberculosis GyrB binding pocket to inhibitor binding. The python script (MMPBSA.py) (72) in the AMBER20 program was used to perform pairwise energy decomposition (idecomp = 4) using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method. Snapshots extracted every 40 ps over the equilibrium state of the MD simulation of enzyme–inhibitor complex were used for energy decomposition. The pairwise decomposition energy includes the gas-phase and solvation interaction energies but does not include the entropic contribution. The gas-phase interaction energies, including the van der Waals (ΔGvdW) and electrostatic (ΔGele) contributions, were computed using the Sander program in AMBER20. The solvation interaction energies, including the contributions of polar (ΔGele,sol) and non-polar solvation (ΔGnonpol,sol), were calculated by using the generalized Born (GB) model (GBOBC model II, igb = 5) (73) and the solvent accessible surface area (SASA) method, (74) respectively.

3. Results and Discussion

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3.1. Ligand-Based Virtual Screening

The ligand-based virtual screening workflow employed here for discovery of M. tuberculosis DNA gyrase ATPase inhibitors is shown in Figure 1. Initially, a structural similarity search (at 60% similarity) using compound G24 as the template was used to select 277 compounds from the Specs database (total 492,534 compounds). The results were then filtered by application of Lipinski’s rule of five (47,75) and PAINS (76) filtering, to yield 40-five compounds. The PubChem web interface was then interrogated to establish the extent of prior biological activity data for these compounds. At the time of enquiry PubChem reported activity assay results against M. tuberculosis growth for 14 compounds, of which three were active and 11 inactive (Table S2), while results for 30-one compounds were not reported. Thus, all 14 previously tested compounds were removed from further investigation, while the remaining 30-one compounds were used for structural clustering. Seventeen of these 30-one compounds that resembled the 11 inactive compounds (Tanimoto coefficient ≥0.5) were removed, yielding 14 hit compounds (Figure 2). These hit compounds are classified into three groups including carbazole derivatives (compounds 1–8), benzoindole derivatives (compounds 9–11), and indole derivatives (compounds 12–14). Previously described inhibitors of M. tuberculosis DNA gyrase ATPase activity include quinoline, (17−19) aminopiperidine, (20) thiazole, (21−23) pyrrolamide, (24) benzofurans, (25,26) benzo[d]isothiazole, (25) benzimidazole, (27) phenylthiophene, (28,29) and pyrimido[4,5-b]indol-8-amine (30,31) scaffolds, as well as benzoindole (32) and indole derivatives (G24 and G26) (33) as we recently identified. Thus, carbazole derivatives (compounds 1–8) can be considered a new (previously unreported) class of M. tuberculosis DNA gyrase ATPase inhibitors.

3.2. Biological Assays

MIC values for the 14 hit compounds were evaluated against the avirulent H37Ra M. tuberculosis strain. Ten of the 14 hits showed MIC values in the range 3.1–25.0 μg/mL. These results indicate that these ten compounds are significantly more active against M. tuberculosis than the well-characterized DNA gyrase ATPase inhibitor novobiocin (34) (MIC > 100 μg/mL; Figure 2). While novobiocin is considered a weaker ATPase inhibitor than the alternative natural aminocoumarins clorobiocin and coumermycin (77,78); the MIC values above compare favorably with those reported for M. tuberculosis growth inhibition by coumermycin A1 (2.5 μg/mL (79)), particularly when considering the distinct mode of action of coumermycin A1, that binds simultaneously to two GyrB ATPase sites. (80)
Next, IC50 values for all ten active compounds were evaluated for inhibition of M. tuberculosis DNA gyrase ATPase activity, to verify this as their target enzyme. Six of the ten tested compounds (1, 2, 3, 8, 11, and 14) inhibited M. tuberculosis DNA gyrase ATPase activity, with IC50 values 0.73, 1.34, 3.82, 0.26, 0.56, and 0.08 μM, respectively (Figure 3; details of fits are provided in Table S3). In comparison, the IC50 value for novobiocin was measured to be 1.27 μM (Figure 3), within the range of values for ATPase inhibition reported by others (0.02 (30); 0.21 (31); 4.21 μM (81)) using various assay methodologies and M. tuberculosis gyrase constructs. These data demonstrate that six of the identified compounds are active in both whole cell growth and enzyme inhibition assays and suggest that their anti-tubercular activity is likely to arise from inhibition of the ATPase activity of M. tuberculosis DNA gyrase.

Figure 3

Figure 3. Inhibition of M. tuberculosis DNA gyrase ATPase activity. IC50 curves for inhibition of M. tuberculosis DNA gyrase ATPase activity by compounds 1, 2, 3, 8, 11, 14, G24, and novobiocin. IC50 values were obtained from nonlinear regression fitting of % inhibition to log of the inhibitor concentration. Error bars represent standard deviations (N = 3). Note that in some cases, these are obscured by symbols. Further details of fit parameters are given in Table S3.

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3.3. Cytotoxicity of Lead Compounds

The six lead compounds, including four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14, that showed activities against M. tuberculosis growth and DNA gyrase ATPase activity, were selected for evaluation of their cytotoxicity toward Caco-2 cells. All of the compounds were non-cytotoxic toward Caco-2 cells at maximum concentrations of 25.0, 12.5, 12.5, 12.5, 0.87, and 12.5 μg/mL, respectively (Figure S1). Two carbazole derivatives (1 and 2) and the indole derivative 14 display maximum non-cytotoxic concentrations (25.0, 12.5, and 12.5 μg/mL, respectively) higher than their MIC values (6.2, 6.2, and 3.1 μg/mL, respectively). The maximum non-cytotoxic concentration of the carbazole derivative 3 is equivalent to the MIC value of 12.5 μg/mL, whereas those of carbazole derivative 8 and benzoindole derivative 11 (12.5 and 0.87 μg/mL, respectively) are lower than the MIC values (25.0 and 3.1 μg/mL, respectively).

3.4. Interactions of Inhibitors with M. tuberculosis DNA Gyrase B

Compound 8, the carbazole derivative showing the most potent inhibition of M. tuberculosis DNA gyrase ATPase activity, was selected for analysis of its interactions with the M. tuberculosis GyrB ATP binding site using molecular dynamics (MD) simulations. The benzoindole derivative 11 and the indole derivative 14, that were also active against M. tuberculosis DNA gyrase ATPase activity, were also selected for further analysis using MD simulations. As all of these are chiral compounds, the binding modes of compounds 8 (carbazole derivative), 11 (benzoindole derivative), and 14 (indole derivative) were considered in both the R and S configurations. The stabilities of MD simulations of the complexes with each compound, with initial structures generated by molecular docking using Glide XP, are provided in Supporting Information (Figure S2). The binding free energies of these compounds to the GyrB 47 kDa fragment, in both stereochemical configurations, in their equilibrium states, were then calculated using the ΔGPBSA and ΔGGBSA methods (Table 1). The average binding free energies calculated for the carbazole derivative 8, the benzoindole derivative 11, and the indole derivative 14 binding to the M. tuberculosis DNA gyrase GyrB ATP site in the R configuration are significantly lower than those obtained for the S configuration, indicating the R stereomer to be the higher affinity configuration in each case. The binding modes of compounds 8, 11, and 14, each in the R configuration, were then analyzed and compared. The binding modes for these three compounds resemble that of our previously described indole derivative G24 (33) (Figure 4A,D,G). Further, compounds 8, 11, and 14 also all partially overlap with the adenosine group of the ATP analogue AMP-PCP when complexed with M. tuberculosis GyrB (PDB code 3ZM7). (58) Notably, the hydrogen bond donating moieties (hydroxyl and amine groups) of these compounds are located near the carboxylate side chain of Asp79, the key residue forming a hydrogen bond interaction with the adenine NH2 group of AMP-PCP (Figure 4B,E,H). Hydrogen bond analysis performed on the MD simulation trajectories of the carbazole derivative 8, benzoindole derivative 11, and indole derivative 14 (Table S4) showed that these compounds can all form hydrogen bonds with the carboxylate oxygen atoms of Asp79 (Figure 4C,F,I), with occupancies more than 60% (Table S4). The contribution of this residue to the binding of compounds 8, 11, and 14 was then further investigated using decomposition energy calculations. The results showed that Asp79 is the GyrB residue that makes the most prominent contribution to the binding of all of these compounds to M. tuberculosis DNA gyrase GyrB, as evidenced by the low decomposition energy values of −30.2 ± 2.0, −19.9 ± 0.6, and −29.8 ± 0.1 kcal/mol, respectively (Figure S3). Thus, hydrogen bond interactions with Asp79 appear crucial for binding of all three compounds to the M. tuberculosis DNA gyrase GyrB subunit. Further, MD simulations were conducted on GyrB with the Asp79Ala (D79A) mutation, bound with compounds 8, 11, and 14 in the R configuration, to support the role of Asp79. The mutation from Asp79 to Ala79 disrupts the hydrogen bonds of these compounds to Asp79 in wild-type GyrB. This disruption is evidenced by the lower contribution of Ala79 to the binding of compounds 8, 11, and 14 with the higher decomposition energy values of −0.1, 0.1, and 0.1 kcal/mol, respectively (Figure S3). Further, the calculated binding free energies of these compounds to the mutant GyrB subunit using the ΔGGBSA and ΔGPBSA methods are significantly higher than those of the wild-type GyrB subunit (Table S5). These results indicate the diminished affinity binding of compounds 8, 11, and 14 for the D79A mutant GyrB subunit, emphasizing the significance of Asp79 as a key residue for high-affinity binding to the M. tuberculosis DNA gyrase GyrB subunit. Similar hydrogen bond interactions with Asp79 are also observed in the binding of three known M. tuberculosis DNA gyrase ATPase inhibitors, pyrrolamide (PDB code 4BAE), (24) aminopyrazinamide (PDB code 4B6C), (59) and novobiocin (PDB code 6Y8O) (31) as shown in Figure S4. Further, these interactions are observed in the binding of DNA gyrase ATPase inhibitors against other bacteria such as S. aureus, (82−84) E. coli, (85−87) and S. pneumoniae. (88) Notably, the IC50 values for inhibition of M. tuberculosis DNA gyrase ATPase activity by compounds 8, 11, and 14 (0.26, 0.56, and 0.08 μM, respectively) that are all predicted to form hydrogen bonds with Asp79, were superior to that obtained for the indole derivative G24 (IC50 2.69 μM, Figure 3) that in previous work was not predicted to form a hydrogen bond with Asp79. (33) These results identify Asp79 as a key residue for high-affinity binding of all three compounds to the M. tuberculosis DNA gyrase GyrB subunit, and consequent inhibition of its ATPase activity. In further support of this conclusion, we note that compounds 9, 10, 12, and 13, all of which lack a hydrogen bond donor at the terminus of their aliphatic substituent groups, are all inactive in ATPase inhibition assays.
Table 1. Binding Free Energy (ΔGGBSA and ΔGPBSA) Calculations from MD Simulations for Lead Compounds
compoundΔGGBSA (kcal/mol)ΔGPBSA (kcal/mol)
replicateaverageareplicateaveragea
123123
8R–57.5–58.9–61.1–59.1 ± 1.8–46.2–48.5–50.4–48.3 ± 2.1
8S–48.4–49.3–48.6–48.8 ± 0.5–48.4–48.5–46.7–47.9 ± 1.0
11R–64.8–60.7–61.4–62.3 ± 2.2–57.1–55.3–56.1–56.2 ± 0.9
11S–55.3–50.1–50.5–52.0 ± 2.9–56.6–52.8–53.4–54.3 ± 2.0
14R–72.0–73.0–71.8–72.3 ± 0.6–62.0–62.8–62.0–62.3 ± 0.5
14S–62.3–62.7–62.6–62.5 ± 0.2–58.1–58.0–57.5–57.8 ± 0.3
a

Errors are estimated from the average and the difference between the results from three separate MD simulations for each compound. R and S represent R and S configurations.

Figure 4

Figure 4. Superimpositions of AMP-PCP, indole derivatives G24, and compounds 8(R), 11(R), and 14(R) in the M. tuberculosis DNA gyrase ATP binding site. (A), (D), and (G) Superimpositions of previously described indole derivative (G24, R configuration, light pink stick) and compounds 8(R), 11(R), and 14(R) (cyan green, magenta, and pale yellow sticks) in the M. tuberculosis GyrB ATP binding site. Binding modes are predicted from MD simulations. (B), (E), and (H) Superimposition of AMP-PCP (PDB 3ZM7, (58) marine sticks) and compounds 8(R), 11(R), and 14(R) (cyan green, magenta, and pale yellow sticks, binding modes predicted from MD simulations). (C), (F), and (I) Hydrogen bond interactions (dashed red arrows) of compounds 8(R), 11(R), and 14(R) with Asp79.

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3.5. Structure–Activity Relationship (SAR)

We utilized our previously discovered indole derivative G24 (33) as the template for virtual screening, leading to the identification of the indole derivative 14 in the present work. The structural similarity between the indole derivatives G24 and 14 is their 1-(5-methyl-2,3-diphenyl-1H-indol-1-yl)propan-2-ol core, whereas the two compounds are distinguished by differences in their hydroxyalkyl amine substituents (Figure 2). Due to this structural difference, compound 14 exhibited improved IC50 and MIC values compared to G24. This identifies the hydroxyalkyl amine substituent as important for enhancing the activity of indole derivative 14 against both M. tuberculosis growth and DNA gyrase ATPase activity. The mode of binding of indole derivative 14 obtained from MD simulations reveals that this substituent is utilized for forming hydrogen bond interactions with Asp79, the key residue for binding to DNA gyrase GyrB subunit. The significance of the hydroxyalkyl amine substituent in mediating the inhibition of DNA gyrase ATPase activity is evidenced by the IC50 values of the indole derivatives 12 and 13 (Figure 2). These derivatives lack the hydroxyalkyl amine substituent, and any terminal hydrogen bond donating group at the termini of their equivalent substituents. The absence of any observed IC50 values may then result from the consequent impaired ability of these compounds to make hydrogen bonds to Asp79. Furthermore, the equivalent substituent is also a determinant of ATPase inhibitory activity (IC50 values) for the benzoindole derivatives also identified in the present work. Specifically, the benzoindole derivative 11, which presents a hydroxyalkyl amine group, yielded a measurable IC50 value, whereas IC50 values for ATPase inhibition could not be determined for the benzoindole derivatives 9 and 10. Of interest, however, the benzoindole and indole derivatives (9, 10, 12, and 13) that lack the hydroxyalkyl amine substituent all gave MIC values for inhibition of M. tuberculosis growth, despite the absence of observable ATPase inhibition, suggesting that for these compounds anti-tubercular activity is unlikely to arise from inhibition of DNA gyrase GyrB ATPase activity. In contrast, the benzoindole derivative 11 and the indole derivative 14 that present the hydroxyalkyl amine substituent are active against both M. tuberculosis growth and DNA gyrase ATPase activity, supporting the latter as the likely basis of their anti-tubercular activity.
The carbazole derivatives identified in the present work represent a new class of M. tuberculosis DNA gyrase ATPase inhibitors. The carbazole derivatives 1–3 and 8 are all active against both M. tuberculosis growth and DNA gyrase ATPase activity, whereas the carbazole derivatives 4–7 showed no anti-tubercular activity (MIC values >100 μg/mL) and their IC50 values for ATPase inhibition were consequently not determined (Figure 2). The carbazole derivatives 1–7 contain equivalent 1-amino-3-(9H-carbazol-9-yl)propan-2-ol cores. Remarkably, carbazole derivatives 1–3, that present methyl, ethyl, or oxyethyl linkers connecting the aliphatic amine to the terminal aromatic ring are all active against M. tuberculosis growth, whereas carbazole derivatives 4–7 with alternative linkers are not. These results indicate that the alkyl linker in the carbazole derivatives 1–3 is important to activity against M. tuberculosis growth. The carbazole derivative 8, that possesses a chemical structure different to those of the other carbazole derivatives tested, contains a hydroxyalkyl amine substituent (Figure 2). This compound inhibited M. tuberculosis DNA gyrase ATPase activity approximately 3, 5, and 15-fold more effectively than the carbazole derivatives 1–3, respectively. The mode of binding of carbazole derivative 8 obtained from MD simulations reveals that this substituent can be utilized to form hydrogen bond interactions with Asp79, as also observed in the binding of both the benzoindole and indole derivatives (Figure 4). Thus, across all three compound classes (carbazole, benzoindole, and indole derivatives) studied here, the hydroxyalkyl amine substituent is important to inhibitory activity toward the ATPase activity of M. tuberculosis DNA gyrase.

4. Conclusions

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Ligand-based virtual screening supported by subsequent whole cell and enzyme inhibition assays identified six compounds that showed anti-tubercular activity and inhibition of the ATPase activity of M. tuberculosis DNA gyrase. This approach yielded a higher percentage (43%) of hits to leads active against both the growth of M. tuberculosis and ATPase activity compared to our two previous works. (32,33) The identified lead compounds are classified as carbazole, benzoindole, and indole derivatives, of which carbazole derivatives represent a new scaffold for inhibition of M. tuberculosis DNA gyrase ATPase activity. The complexes of carbazole, benzoindole, and indole derivatives bound to the ATP binding site of the M. tuberculosis DNA gyrase GyrB subunit, modeled by MD simulations, highlighted the critical role of hydrogen bond interactions with Asp79 in binding. SAR analysis suggests that the hydroxyalkyl amine substituents of the benzoindole and indole derivatives, that our models implicate in hydrogen bonding to Asp79, are important to inhibition of DNA gyrase ATPase activity. In the case of the carbazole derivatives, the equivalent hydroxyalkyl amine substituent similarly enhances IC50 values for inhibition of DNA gyrase ATPase activity, while an alkyl linker appears crucial to inhibition of M. tuberculosis growth. The importance to inhibitor binding of the conserved Asp79 is noteworthy given the involvement of this residue in interactions with ATP; previous investigations identify that substitution of the equivalent position in E. coli reduces susceptibility to novobiocin inhibition, but is sufficiently detrimental to ATPase activity for selection of such mutations in vivo to be considered unlikely. (89) Thus, ATPase inhibitors that, as here, derive much of their potency from hydrogen bonding to Asp79 might be at reduced risk of failure through mutational resistance. Taken together, our findings support similarity-based virtual screening as a valid and efficient tool with which to improve inhibitors of M. tuberculosis DNA gyrase ATPase activity, that retains the ability to identify new scaffolds able to inhibit this validated, but clinically under-exploited, target.

Data Availability

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All chemical structures in SDF format of small molecules were downloaded from Specs database (https://www.specs.net/). PAINS and physicochemical properties of these molecules were calculated by SwissADME (http://www.swissadme.ch/index.php). (47) 2D chemical structures of small molecules in Figure 2 were generated using ChemDraw 20.1.1 (CambridgeSoft, http://www.cambridgesoft.com). IC50 values were calculated using GraphPad Prism8 with free trial license (GraphPad Inc., https://www.graphpad.com/) in Figure 3. Figures 4 and S4 were generated using pyMOL2.2.0 (https://pymol.org/2/).

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.4c00511.

  • Hit compound cytotoxicity against Caco-2 cells; cells were incubated with different concentrations of compounds (1, 2, 3, 8, 11, 14, G24, and G26) for 24 h and viability measured by MTT assay; all-atom RMSD plots for MD simulations of M. tuberculosis GyrB:inhibitor complexes; per-residue analysis of inhibitor:GyrB interactions; hydrogen bond interactions of known ATPase inhibitors with Asp79 in the M. smegmatis DNA gyrase ATP binding site; hits and leads obtained from three different virtual screening methods; previously characterized compounds identified from virtual similarity screening; details of fit parameters for IC50 determinations; hydrogen bonding of most active compounds (R-stereomers) to GyrB Asp79; and calculated binding free energies for binding of compounds 8, 11, and 14 to the wild type and mutant (D79A) GyrB subunits (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Bongkochawan Pakamwong - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand;  Orcidhttps://orcid.org/0000-0003-0383-8645
    • Paptawan Thongdee - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand;  Orcidhttps://orcid.org/0000-0003-0824-4651
    • Bundit Kamsri - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand;  Orcidhttps://orcid.org/0000-0002-5890-2619
    • Naruedon Phusi - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand;  Orcidhttps://orcid.org/0000-0002-5940-1082
    • Somjintana Taveepanich - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
    • Kampanart Chayajarus - Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
    • Pharit Kamsri - Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand;  Orcidhttps://orcid.org/0000-0001-5233-3892
    • Auradee Punkvang - Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand;  Orcidhttps://orcid.org/0000-0002-0325-9179
    • Supa Hannongbua - Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;  Orcidhttps://orcid.org/0000-0002-9901-4466
    • Jidapa Sangswan - Department of Biological Science, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
    • Khomson Suttisintong - National Nanotechnology Center, NSTDA, 111 Thailand Science Park, Klong Luang, Pathum Thani 12120, Thailand;  Orcidhttps://orcid.org/0000-0002-8797-6959
    • Sanya Sureram - Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand;  Orcidhttps://orcid.org/0000-0001-8717-5097
    • Prasat Kittakoop - Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand;  Program in Chemical Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand;  Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10210, Thailand;  Orcidhttps://orcid.org/0000-0002-5210-3162
    • Poonpilas Hongmanee - Division of Clinical Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;  Orcidhttps://orcid.org/0000-0001-5086-0111
    • Pitak Santanirand - Division of Clinical Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
    • Jiraporn Leanpolchareanchai - Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
    • James Spencer - School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, U.K.;  Orcidhttps://orcid.org/0000-0002-4602-0571
    • Adrian J. Mulholland - Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.;  Orcidhttps://orcid.org/0000-0003-1015-4567
  • Author Contributions

    B.P. performed computational calculations, protein expression, protein purification, characterization, biological assay, and wrote the manuscript. P.T. and B.K. performed protein expression, protein purification, characterization, and biological assays. N.P. performed protein expression, purification, characterization, biological assays, and revised the manuscript. S.T. and K.C. wrote, revised, and edited the manuscript. P.K. performed computational calculations and revised the manuscript. A.P. performed computational calculations, wrote, revised, and edited the manuscript. S.H. and K.S. revised and edited the manuscript. J.S. performed protein expression, protein purification, characterization, and biological assays, and wrote and edited the manuscript. S.S., P.H., and P.S. performed MIC assays. P.K. performed MIC assays and revised and edited the manuscript. J.L. performed the in vitro cytotoxicity study and wrote and edited the manuscript. J.S. wrote, revised, and edited the manuscript. A.J.M. provided computational resources and revised and edited the manuscript. P.P. provided conceptualization, supervision, resources, project administration, and funding acquisition; and wrote, revised, and edited the manuscript. All authors participated in the discussion and interpretation of the results. All authors edited and proofread the final manuscript.

  • Funding

    Thailand Science Research and Innovation (TSRI), National Science, Research and Innovation Fund (NSRF) Center of Excellence for Innovation in Chemistry (PERCH-CIC) Thailand Science Research and Innovation (TSRI, Chulabhorn Research Institute (Grant No. 36827/4274406) Royal Golden Jubilee Ph.D. Program (PHD/0155/2560 and PHD/0132/2559) The Thailand Graduate Institute of Science and Technology (TGIST) (SCA-CO-2561-6946-TH and SCA-CO-2563-12135-TH) Engineering and Physical Sciences Research Council (EP/M022609/1) Biotechnology and Biological Sciences Research Council (BB/Y514123/1) The European Research Council under the European Horizon 2020 research and innovation program (PREDACTED Advanced Grant Agreement no. 101021207) Ubon Ratchathani University

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research was supported by the Thailand Science Research and Innovation (TSRI), National Science, Research and Innovation Fund (NSRF), Center of Excellence for Innovation in Chemistry (PERCH-CIC) and Ubon Ratchathani University, Thailand. This work is partially supported by Thailand Science Research and Innovation (TSRI, Chulabhorn Research Institute (Grant No. 36827/4274406). The financial support from Royal Golden Jubilee Ph.D. Program, Thailand to B.P. (PHD/0155/2560) and B.K. (PHD/0132/2559) is gratefully acknowledged. The Thailand Graduate Institute of Science and Technology, Thailand (SCA-CO-2561-6946-TH and SCA-CO-2563-12135-TH) is acknowledged for financial support to P.T. and N.P., respectively. We thank EPSRC (CCP-BioSim, grant number EP/M022609/1) and BBSRC (International Institutional Award, BB/Y514123/1) for support. A.J.M. and J.S. thank the European Research Council under the European Horizon 2020 research and innovation programme (PREDACTED Advanced Grant Agreement no. 101021207). All MD simulations were carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol, United Kingdom http://www.bris.ac.uk/acrc/. Ubon Ratchathani University, NECTEC, Thailand, and the University of Bristol, United Kingdom are gratefully acknowledged for supporting this research.

Abbreviations

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TB

tuberculosis

MDR-TB

multidrug-resistant TB

M. tuberculosis

Mycobacterium tuberculosis

FQ

fluoroquinolones

GyrA

DNA gyrase A

GyrB

DNA gyrase B

MIC

minimal inhibitory concentration

IC50

half-maximal inhibitory concentration

PAINS

pan-assay interference compounds

MABA

microplate alamar blue assay

DMSO

dimethyl sulfoxide

PCR

polymerase chain reaction

E. coli

Escherichia coli

LB

Luria Broth

IPTG

isopropyl-β-D-thiogalactopyranoside

Ni-NTA

nickel-nitrilotriacetic acid

SDS-PAGE

sodium dodecyl sulfate polyacrylamide gel electrophoresis

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

nm

nanometer

MD

molecular dynamics simulations

XP

extra precision

GPU

graphics processing unit

GAFF

general amber force field

RESP

restrained electrostatic potential

RMSD

root-mean square deviation

MM/PBSA

molecular mechanics Poisson–Boltzmann surface area

MM/GBSA

molecular mechanics generalized born surface area

SASA

Solvent accessible surface area

S. aureus

Staphylococcus aureus

S. pneumoniae

Streptococcus pneumoniae

SAR

structure–activity relationship

References

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This article references 89 other publications.

  1. 1
    WHO. Global tuberculosis report 2023. https://www.who.int/publications/i/item/9789240083851 (accessed January 2024).
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Aubry, A.; Fisher, L. M.; Jarlier, V.; Cambau, E. First functional characterization of a singly expressed bacterial type II topoisomerase: the enzyme from Mycobacterium tuberculosis. Biochem. Biophys. Res. Commun. 2006, 348, 158– 165,  DOI: 10.1016/j.bbrc.2006.07.017
    Google Scholar
    2
    First functional characterization of a singly expressed bacterial type II topoisomerase: The enzyme from Mycobacterium tuberculosis
    Aubry, Alexandra; Mark Fisher, L.; Jarlier, Vincent; Cambau, Emmanuelle
    Biochemical and Biophysical Research Communications (2006), 348 (1), 158-165CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)
    Genome deciphering revealed that Mycobacterium tuberculosis encodes a single type II topoisomerase contrary to common bacteria harboring two type II topoisomerases (DNA gyrase and topoisomerase IV). Functions of the M. tuberculosis type II topoisomerase were explored after cloning and expressing the subunits encoding genes in Escherichia coli. M. tuberculosis type II topoisomerase supercoiled relaxed pBR322 with a specific activity close to that of DNA gyrases of common bacteria whereas it exhibited DNA relaxation and formation of cleavable complexes with activities significantly higher than other DNA gyrases. Intermol. passage activity evaluated by the decatenation of kinetoplast DNA was 25-fold lower than that of the topoisomerase IV from Streptococcus pneumoniae, but was markedly higher than that of the E. coli gyrase. Overall, the type II topoisomerase of M. tuberculosis exhibits classical polyvalent activities of DNA gyrase for supercoiling but enhanced relaxation, cleavage, and decatenation activities.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xot1Wqtbg%253D&md5=763bef9f46308f23af208f537e82c1bd
  3. 3
    Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E., 3rd; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M. A.; Rajandream, M. A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.; Taylor, K.; Whitehead, S.; Barrell, B. G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998, 393, 537– 544,  DOI: 10.1038/31159
    Google Scholar
    3
    Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
    Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E., III; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M. A.; Rajandream, M.-A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.; Taylor, K.; Whitehead, S.; Barrell, B. G.
    Nature (London) (1998), 393 (6685), 537-544CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
    Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, was detd. and analyzed in order to improve our understanding of the biol. of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4000 genes, and has a very high G+C content that is reflected in the biased amino acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the prodn. of enzymes involved in lipogenesis and lipolysis, and to 2 new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjvV2ksrY%253D&md5=44d23e7674bfeb1a3e30b55abf5268d2
  4. 4
    Bush, N. G.; Evans-Roberts, K.; Maxwell, A. DNA Topoisomerases. EcoSal Plus 2015, 6, 1– 34,  DOI: 10.1128/ecosalplus.esp-0010-2014
    Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Asif, M.; Siddiqui, A. A.; Husain, A. Quinolone derivatives as antitubercular drugs. Med. Chem. Res. 2013, 22, 1029– 1042,  DOI: 10.1007/s00044-012-0101-3
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Facchinetti, V.; Gomes, C. R. B.; de Souza, M. V. N.; Vasconcelos, T. R. A. Perspectives on the development of novel potentially active quinolones against tuberculosis and cancer. Mini-Rev. Med. Chem. 2012, 12, 866– 874,  DOI: 10.2174/138955712800959099
    Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Kathrotiya, H. G.; Patel, M. P. Synthesis and identification of β–aryloxyquinoline based diversely fluorine substituted N–aryl quinolone derivatives as a new class of antimicrobial, antituberculosis and antioxidant agents. Eur. J. Med. Chem. 2013, 63, 675– 684,  DOI: 10.1016/j.ejmech.2013.03.017
    Google Scholar
    There is no corresponding record for this reference.
  8. 8
    Kim, O. K.; Ohemeng, K.; Barrett, J. F. Advances in DNA gyrase inhibitors. Expert Opin. Investig. Drugs. 2001, 10, 199– 212,  DOI: 10.1517/13543784.10.2.199
    Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Liu, K. L.; Teng, F.; Xiong, L.; Li, X.; Gao, C.; Yu, L. T. Discovery of quinolone derivatives as antimycobacterial agents. RSC Adv. 2021, 11, 24095– 24115,  DOI: 10.1039/D0RA09250A
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Sriram, D.; Aubry, A.; Yogeeswari, P.; Fisher, L. M. Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase. Bioorg. Med. Chem. Lett. 2006, 16, 2982– 2985,  DOI: 10.1016/j.bmcl.2006.02.065
    Google Scholar
    There is no corresponding record for this reference.
  11. 11
    Huang, T. S.; Kunin, C. M.; Lee, S. S. J.; Chen, Y. S.; Tu, H. Z.; Liu, Y. C. Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995–2003. J. Antimicrob. Chemother. 2005, 56, 1058– 1062,  DOI: 10.1093/jac/dki353
    Google Scholar
    11
    Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995-2003
    Huang, Tsi-Shu; Kunin, Calvin M.; Lee, Susan Shin-Jung; Chen, Yao-Shen; Tu, Hui-Zin; Liu, Yung-Ching
    Journal of Antimicrobial Chemotherapy (2005), 56 (6), 1058-1062CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    Fluoroquinolones are being used more frequently for the treatment of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis complex (MTB). This study was designed to det. the frequency of the emergence of fluoroquinolone-resistant strains in Taiwan and to assess whether this might be due to use of fluoroquinolones for treatment of patients with MDR or because of increased use of fluoroquinolones in the community for treatment of other infections. The authors also sought to det. whether there might be clonal spread of fluoroquinolone resistance. A total of 3497 clin. isolates of M. tuberculosis complex were obtained during 1995-2003, of which 141 were selected. They consisted of 62 isolates fully susceptible to four first-line drugs, 33 isolates resistant to rifampicin and isoniazid (MDR), and 46 isolates with a variety of any drug resistant patterns other than MDR (combination group). The MICs were detd. for ciprofloxacin, ofloxacin and levofloxacin. Results: An increase in the MIC90 and rates of resistance to ciprofloxacin, ofloxacin and levofloxacin were noted only in the MDR group. The rates were higher among strains isolated between 1998-2003 compared with those obtained between 1995-1997 (rate of resistance, 20% vs. 7.7%; MIC ≥ 4 mg/L vs. 1-2 mg/L). Among the 10 fluoroquinolone-resistant isolates, 5 (50%) possessed mutations other than S95T in the gyrA gene. No gyrB mutation was found in any of the clin. isolates. These findings suggest that fluoroquinolone resistance is the result of treatment of patients with MDR strains rather than from use in the general community in Taiwan. The emergence of fluoroquinolone resistance among MDR strains reinforces the need for routine fluoroquinolone susceptibility testing whenever these drugs might be used.
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  12. 12
    Lee, A. S.; Tang, L. L.; Lim, I. H.; Wong, S. Y. Characterization of pyrazinamide and ofloxacin resistance among drug resistant Mycobacterium tuberculosis isolates from Singapore. Int. J. Infect. Dis. 2002, 6, 48– 51,  DOI: 10.1016/s1201-9712(02)90136-0
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    12
    Characterization of pyrazinamide and ofloxacin resistance among drug resistant Mycobacterium tuberculosis isolates from Singapore
    Lee Ann S G; Tang Lynn L H; Lim Irene H K; Wong Sin Yew
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (2002), 6 (1), 48-51 ISSN:1201-9712.
    OBJECTIVES: To evaluate rapid molecular approaches for the detection of pyrazinamide (PZA) and ofloxacin resistance, by screening 100 known drug-resistant Mycobacterium tuberculosis isolates. METHODS: Mycobacterium tuberculosis isolates were tested for phenotypic resistance to pyrazinamide and ofloxacin using the BACTEC 460 radiometric method and the E-test, respectively. Mutation screening was done by amplifying the pncA, gyrA, and gyrB genes by the polymerase chain reaction (PCR) and direct automated sequencing. RESULTS: Twelve isolates were PZA-resistant and 8 of 12 (66.7%) isolates had missense mutations or deletions at the pncA gene, suggesting that mutation or deletion at the pncA gene is the major molecular mechanism of PZA resistance among the Singaporean isolates. Using the E-test, 48 isolates were resistant to ofloxacin, with minimum inhibitory concentrations of 4 microg/mL or higher. No mutations were observed at the quinolone resistance-determining region (QRDR) of gyrA in all isolates. At the QRDR of gyrB, mutations were present in 1 of 48 ofloxacin-resistant isolates and 0 of 19 ofloxacin-susceptible isolates. CONCLUSIONS: In Singapore, genotypic analysis of resistance to PZA and ofloxacin is inadequate and should be complemented by conventional methods.
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  13. 13
    Maruri, F.; Sterling, T. R.; Kaiga, A. W.; Blackman, A.; van der Heijden, Y. F.; Mayer, C.; Cambau, E.; Aubry, A. A systematic review of gyrase mutations associated with fluoroquinolone–resistant Mycobacterium tuberculosis and a proposed gyrase numbering system. J. Antimicrob. Chemother. 2012, 67, 819– 831,  DOI: 10.1093/jac/dkr566
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    13
    A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system
    Maruri, Fernanda; Sterling, Timothy R.; Kaiga, Anne W.; Blackman, Amondrea; van der Heijden, Yuri F.; Mayer, Claudine; Cambau, Emmanuelle; Aubry, Alexandra
    Journal of Antimicrobial Chemotherapy (2012), 67 (4), 819-831CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    Fluoroquinolone resistance in Mycobacterium tuberculosis has become increasingly important. A review of mutations in DNA gyrase, the fluoroquinolone target, is needed to improve the mol. detection of resistance. The authors performed a systematic review of studies reporting mutations in DNA gyrase genes in clin. M. tuberculosis isolates. From 42 studies that met inclusion criteria, 1220 fluoroquinolone-resistant M. tuberculosis isolates underwent sequencing of the quinolone resistance-detg. region (QRDR) of gyrA; 780 (64%) had mutations. The QRDR of gyrB was sequenced in 534 resistant isolates; 17 (3%) had mutations. Mutations at gyrA codons 90, 91 or 94 were present in 654/1220 (54%) resistant isolates. Four different GyrB numbering systems were reported, resulting in mutation location discrepancies. The authors propose a consensus numbering system. Most fluoroquinolone-resistant M. tuberculosis isolates had mutations in DNA gyrase, but a substantial proportion did not. The proposed consensus numbering system can improve mol. detection of resistance and identification of novel mutations.
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  14. 14
    Pitaksajjakul, P.; Wongwit, W.; Punprasit, W.; Eampokalap, B.; Peacock, S.; Ramasoota, P. Mutations in the GyrA and GyrB genes of fluoroquinolone–resistant Mycobacterium tuberculosis from TB patients in Thailand. Southeast Asian J. Trop. Med. Public Health 2005, 36, 228– 237
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    14
    Mutations in the gyrA and gyrB genes of fluoroquinolone-resistant Mycobacterium tuberculosis from TB patients in Thailand
    Pitaksajjakul, Pannamthip; Wongwit, Waranya; Punprasit, Wantanee; Eampokalap, Boonchuy; Peacock, Sharon; Ramasoota, Pongrama
    Southeast Asian Journal of Tropical Medicine and Public Health (2005), 36 (Suppl. 4), 228-237CODEN: SJTMAK; ISSN:0125-1562. (SEAMEO-TROPMED Network)
    Among fluoroquinolone-resistant Mycobacterium tuberculosis (FQr-MTB) isolates, mutation at positions 90, 91, and 94 in gyrA gene and at positions 495, 516, and 533 in gyrB gene have been frequently reported. In this study, 35 isolates of FQr-MTB were collected from Siriraj Hospital and Chest Disease Institute. The quinolone-resistance-detg. regions (QRDR) of gyrA and gyrB genes in all 35 FQr-MTB isolates and from the H37Ra MTB strain were amplified using polymerase chain reaction (PCR). DNA-sequencing and single-strand conformation polymorphism (SSCP) were further utilized for characterization of the mutations in the QRDR of gyrA and gyrB genes and mutation screening, resp. From DNA-sequencing, 21 of 35 (60%) exhibited single-point mutations in different positions, at Ala90Val, Ser91Pro, and Asp94(Gly/Ala/His/Asn); and one novel mutation position at Gly88Cys in the gyrA gene and Asp495Asn in the gyrB gene. These positions were previously frequently reported to be responsible for FQr-MTB. The other 14 FQr-MTB isolates (40%) had no mutation. This study is the first report of mutation occurring only in the QRDR of the gyrB gene, without prior mutation in the gyrA QRDR among FQr-MTB isolates. By SSCP anal. for screening of the mutant FQr-MTB, the SSCP patterns of mutated FQr-MTB isolates were clearly differentiated from the SSCP patterns of FQs-MTB.
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  15. 15
    Pitaksajjakul, P.; Worakhunpiset, S.; Chaiprasert, A.; Boonyasopun, J.; Ramasoota, P. GyrA and GyrB mutations in ofloxacin–resistant Mycobacterium tuberculosis clinical isolates in Thailand. Southeast Asian J. Trop. Med. Public Health. 2011, 42, 1163– 1167
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    15
    gyrA and gyrB mutations in ofloxacin-resistant Mycobacterium tuberculosis clinical isolates in Thailand
    Pitaksajjakul, Pannamthip; Worakhunpiset, Suwalee; Chaiprasert, Angkana; Boonyasopun, Jirakarn; Ramasoota, Pongrama
    Southeast Asian Journal of Tropical Medicine and Public Health (2011), 42 (5), 1163-1167CODEN: SJTMAK; ISSN:0125-1562. (SEAMEO-TROPMED Network)
    In order to identify mutations in gyrA and gyrB genes in 92 ofloxacin-resistant Mycobacterium tuberculosis (OFXr-MTB) clin. isolates collected from Siriraj Hospital, Mahidol University and Chest Disease Institute, Thailand. The quinolone resistance-detg. regions (QRDR) of gyrA and gyrB in all 92 OFXr-MTB isolates were amplified using polymerase chain reaction and sequenced. There were 70 isolates with point mutations assocd. with ofloxacin resistance. In gyrA QRDR, 69 isolates had mutations in gyrA Gly88 (Ala/(75), Ala90 (Val), Ser91 (Pro) and Asp94 (Gly/Ala/His/Asn), the latter being the most common (42%). Only one isolate was found with mutation at position Asp495 (Asn). The other 22 isolates had no mutations in both gyrA and gyrB QRDR. Thus, point mutations in gyrA and gyrB QRDR were responsible for OFXr-MTB clin. isolates in Thailand.
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  16. 16
    Soudani, A.; Hadjfredj, S.; Zribi, M.; Messaoud, T.; Masmoudi, A.; Majed, B.; Fendri, C. First report of molecular characterization of fluoroquinolone–resistant Mycobacterium tuberculosis isolates from a Tunisian hospital. Clin. Microbiol. Infect. 2010, 16, 1454– 1457,  DOI: 10.1111/j.1469-0691.2010.03087.x
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    There is no corresponding record for this reference.
  17. 17
    Medapi, B.; Renuka, J.; Saxena, S.; Sridevi, J. P.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Design and synthesis of novel quinoline–aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyrase B inhibitors. Bioorg. Med. Chem. 2015, 23, 2062– 2078,  DOI: 10.1016/j.bmc.2015.03.004
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    There is no corresponding record for this reference.
  18. 18
    Medapi, B.; Suryadevara, P.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. 4–Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation. Eur. J. Med. Chem. 2015, 103, 1– 16,  DOI: 10.1016/j.ejmech.2015.06.032
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    There is no corresponding record for this reference.
  19. 19
    Jeankumar, V. U.; Reshma, R. S.; Vats, R.; Janupally, R.; Saxena, S.; Yogeeswari, P.; Sriram, D. Engineering another class of anti–tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors. Eur. J. Med. Chem. 2016, 122, 216– 231,  DOI: 10.1016/j.ejmech.2016.06.042
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    There is no corresponding record for this reference.
  20. 20
    Jeankumar, V. U.; Renuka, J.; Pulla, V. K.; Soni, V.; Sridevi, J. P.; Suryadevara, P.; Shravan, M.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Development of novel N–linked aminopiperidine–based mycobacterial DNA gyrase B inhibitors: scaffold hopping from known antibacterial leads. Int. J. Antimicrob Agents. 2014, 43, 269– 278,  DOI: 10.1016/j.ijantimicag.2013.12.006
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    There is no corresponding record for this reference.
  21. 21
    Jeankumar, V. U.; Kotagiri, S.; Janupally, R.; Suryadevara, P.; Sridevi, J. P.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Exploring the gyrase ATPase domain for tailoring newer anti–tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors. Bioorg. Med. Chem. 2015, 23, 588– 601,  DOI: 10.1016/j.bmc.2014.12.001
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    There is no corresponding record for this reference.
  22. 22
    Omar, M. A.; Masaret, G. S.; Abbas, E. M. H.; Abdel Aziz, M. M.; Harras, M. F.; Farghaly, T. A. Novel anti–tubercular and antibacterial based benzosuberone–thiazole moieties: synthesis, molecular docking analysis, DNA gyrase supercoiling and ATPase activity. Bioorg Chem. 2020, 104, 104316  DOI: 10.1016/j.bioorg.2020.104316
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    There is no corresponding record for this reference.
  23. 23
    Jeankumar, V. U.; Renuka, J.; Kotagiri, S.; Saxena, S.; Kakan, S. S.; Sridevi, J. P.; Yellanki, S.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Gyrase ATPase domain as an antitubercular drug discovery platform: structure–based design and lead optimization of nitrothiazolyl carboxamide analogues. Chem. Med. Chem. 2014, 9, 1850– 1859,  DOI: 10.1002/cmdc.201402035
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    There is no corresponding record for this reference.
  24. 24
    P, S. H.; Solapure, S.; Mukherjee, K.; Nandi, V.; Waterson, D.; Shandil, R.; Balganesh, M.; Sambandamurthy, V. K.; Raichurkar, A. K.; Deshpande, A.; Ghosh, A.; Awasthy, D.; Shanbhag, G.; Sheikh, G.; McMiken, H.; Puttur, J.; Reddy, J.; Werngren, J.; Read, J.; Kumar, M.; M, R.; Chinnapattu, M.; Madhavapeddi, P.; Manjrekar, P.; Basu, R.; Gaonkar, S.; Sharma, S.; Hoffner, S.; Humnabadkar, V.; Subbulakshmi, V.; Panduga, V. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure–activity relationship and in vivo efficacy in a mouse model of tuberculosis. Antimicrob. Agents Chemother. 2014, 58, 61– 70,  DOI: 10.1128/AAC.01751-13
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    There is no corresponding record for this reference.
  25. 25
    Reddy, K. I.; Srihari, K.; Renuka, J.; Sree, K. S.; Chuppala, A.; Jeankumar, V. U.; Sridevi, J. P.; Babu, K. S.; Yogeeswari, P.; Sriram, D. An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition. Bioorg. Med. Chem. 2014, 22, 6552– 6563,  DOI: 10.1016/j.bmc.2014.10.016
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    25
    An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition
    Reddy, Kummetha Indrasena; Srihari, Konduri; Renuka, Janupally; Sree, Komanduri Shruthi; Chuppala, Aruna; Jeankumar, Variam Ullas; Sridevi, Jonnalagadda Padma; Babu, Kondra Sudhakar; Yogeeswari, Perumal; Sriram, Dharmarajan
    Bioorganic & Medicinal Chemistry (2014), 22 (23), 6552-6563CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    A series of twenty eight mols. of Et 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by mol. hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorometry. Also the orientation and the ligand-protein interactions of the top hit mols. with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compds. studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a pos. shift of 3.5 °C in differential scanning fluorimetric evaluations.
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  26. 26
    Renuka, J.; Reddy, K. I.; Srihari, K.; Jeankumar, V. U.; Shravan, M.; Sridevi, J. P.; Yogeeswari, P.; Babu, K. S.; Sriram, D. Design, synthesis, biological evaluation of substituted benzofurans as DNA gyrase B inhibitors of Mycobacterium tuberculosis. Bioorg. Med. Chem. 2014, 22, 4924– 4934,  DOI: 10.1016/j.bmc.2014.06.041
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    26
    Design, synthesis, biological evaluation of substituted benzofurans as DNA gyrase B inhibitors of Mycobacterium tuberculosis
    Renuka, Janupally; Reddy, Kummetha Indrasena; Srihari, Konduri; Jeankumar, Variam Ullas; Shravan, Morla; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Babu, Kondra Sudhakar; Sriram, Dharmarajan
    Bioorganic & Medicinal Chemistry (2014), 22 (17), 4924-4934CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well established and validated target for the development of novel therapeutics. The authors present the discovery and optimization of an Et 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyrase B inhibitors, selected from the Birla Institute of Technol. and Science (BITS) database chem. library of about 3000 mols. When these compds. were tested for their biol. activity, the compd. 22 emerged as the most active potent lead with an IC50 of 3.2 ± 0.15 μM against Mycobacterium smegmatis DNA gyrase B enzyme and 0.81 ± 0.24 μM in MTB supercoiling activity. The binding of this most active compd. to the DNA gyrase B enzyme and its thermal stability was further characterized using a differential scanning fluorimetry method.
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  27. 27
    Jeankumar, V. U.; Saxena, S.; Vats, R.; Reshma, R. S.; Janupally, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Structure–guided discovery of antitubercular agents that target the gyrase ATPase domain. Chem. Med. Chem. 2016, 11, 539– 548,  DOI: 10.1002/cmdc.201500556
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    There is no corresponding record for this reference.
  28. 28
    Saxena, S.; Samala, G.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. Development of 2–amino–5–phenylthiophene–3–carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain. Bioorg. Med. Chem. 2015, 23, 1402– 1412,  DOI: 10.1016/j.bmc.2015.02.032
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    There is no corresponding record for this reference.
  29. 29
    Saxena, S.; Renuka, J.; Yogeeswari, P.; Sriram, D. Discovery of novel mycobacterial DNA gyrase B inhibitors: In silico and in vitro biological evaluation. Mol. Inform. 2014, 33, 597– 609,  DOI: 10.1002/minf.201400058
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    There is no corresponding record for this reference.
  30. 30
    McGarry, D. H.; Cooper, I. R.; Walker, R.; Warrilow, C. E.; Pichowicz, M.; Ratcliffe, A. J.; Salisbury, A. M.; Savage, V. J.; Moyo, E.; Maclean, J.; Smith, A.; Charrier, C.; Stokes, N. R.; Lindsay, D. M.; Kerr, W. J. Design, synthesis and antibacterial properties of pyrimido[4,5–b]indol–8–amine inhibitors of DNA gyrase. Bioorg. Med. Chem. Lett. 2018, 28, 2998– 3003,  DOI: 10.1016/j.bmcl.2018.05.049
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    There is no corresponding record for this reference.
  31. 31
    Henderson, S. R.; Stevenson, C. E. M.; Malone, B.; Zholnerovych, Y.; Mitchenall, L. A.; Pichowicz, M.; McGarry, D. H.; Cooper, I. R.; Charrier, C.; Salisbury, A. M.; Lawson, D. M.; Maxwell, A. Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase. J. Antimicrob. Chemother. 2020, 75, 2835– 2842,  DOI: 10.1093/jac/dkaa286
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    31
    Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase
    Henderson, Sara R.; Stevenson, Clare E. M.; Malone, Brandon; Zholnerovych, Yelyzaveta; Mitchenall, Lesley A.; Pichowicz, Mark; McGarry, David H.; Cooper, Ian R.; Charrier, Cedric; Salisbury, Anne-Marie; Lawson, David M.; Maxwell, Anthony
    Journal of Antimicrobial Chemotherapy (2020), 75 (10), 2835-2842CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
    To evaluate the efficacy of two novel compds. against mycobacteria and det. the mol. basis of their action on DNA gyrase using structural and mechanistic approaches. Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallog. was used to det. the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. Both compds., Redx03863 and Redx04739, were active against selected Gram-pos. and Gram-neg. species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compds. were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compds. could have potential to be further exploited as antibiotics.
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  32. 32
    Kamsri, B.; Pakamwong, B.; Thongdee, P.; Phusi, N.; Kamsri, P.; Punkvang, A.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Sangswan, J.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Leanpolchareanchai, J.; Goudar, K. E.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity. J. Chem. Inf Model. 2023, 63, 2707– 2718,  DOI: 10.1021/acs.jcim.2c01376
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    There is no corresponding record for this reference.
  33. 33
    Pakamwong, B.; Thongdee, P.; Kamsri, B.; Phusi, N.; Kamsri, P.; Punkvang, A.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Ariyachaokun, K.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis. J. Chem. Inf Model. 2022, 62, 1680– 1690,  DOI: 10.1021/acs.jcim.1c01390
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    33
    Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis
    Pakamwong, Bongkochawan; Thongdee, Paptawan; Kamsri, Bundit; Phusi, Naruedon; Kamsri, Pharit; Punkvang, Auradee; Ketrat, Sombat; Saparpakorn, Patchreenart; Hannongbua, Supa; Ariyachaokun, Kanchiyaphat; Suttisintong, Khomson; Sureram, Sanya; Kittakoop, Prasat; Hongmanee, Poonpilas; Santanirand, Pitak; Spencer, James; Mulholland, Adrian J.; Pungpo, Pornpan
    Journal of Chemical Information and Modeling (2022), 62 (7), 1680-1690CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Mycobacterium tuberculosis DNA gyrase manipulates the DNA topol. using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biol. assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compd. library (www.specs.net). Thirty compds. were identified and selected as hits for in vitro biol. assays, of which two compds., G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concn. of 12.5 μg/mL. The two compds. inhibited DNA gyrase ATPase activity with IC50 values of 2.69 and 2.46 μM, resp., suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compds. I and II bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by mol. dynamics simulations followed by pharmacophore mapping anal., showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compd. lipophilicity by increasing the polarity of these tails then presents a likely route to improving the soly. and activity. Thus, compds. I and II provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.
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  34. 34
    Maxwell, A. The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 1993, 9, 681– 686,  DOI: 10.1111/j.1365-2958.1993.tb01728.x
    Google Scholar
    34
    The interaction between coumarin drugs and DNA gyrase
    Maxwell, Anthony
    Molecular Microbiology (1993), 9 (4), 681-6CODEN: MOMIEE; ISSN:0950-382X.
    A review with 49 refs. The coumarin group of antibiotics have as their target bacterial DNA gyrase (I). The drugs bind to the B subunit of I and inhibit DNA supercoiling by blocking the ATPase activity. Recent data show that the binding site for the drugs lies within the N-terminal part of the B protein, and individual amino acids involved in coumarin interaction are being identified. The mode of inhibition of the I ATPase reaction by coumarins is unlikely to be simple competitive inhibition, and the drugs may act by stabilizing a conformation of the enzyme with low affinity for ATP.
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  35. 35
    Grossman, S.; Fishwick, C. W. G.; McPhillie, M. J. Developments in non–intercalating bacterial topoisomerase inhibitors: allosteric and ATPase inhibitors of DNA gyrase and topoisomerase IV. Pharm. 2023, 16, 261,  DOI: 10.3390/ph16020261
    Google Scholar
    There is no corresponding record for this reference.
  36. 36
    Kar, S.; Roy, K. How far can virtual screening take us in drug discovery?. Expert Opin Drug Discovery 2013, 8, 245– 261,  DOI: 10.1517/17460441.2013.761204
    Google Scholar
    There is no corresponding record for this reference.
  37. 37
    Lionta, E.; Spyrou, G.; Vassilatis, D. K.; Cournia, Z. Structure–based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top Med. Chem. 2014, 14, 1923– 1938,  DOI: 10.2174/1568026614666140929124445
    Google Scholar
    37
    Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances
    Lionta, Evanthia; Spyrou, George; Vassilatis, Demetrios K.; Cournia, Zoe
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (16), 1923-1938CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the mol. basis of a disease and utilizes the knowledge of the three-dimensional structure of the biol. target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of top scoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.
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  38. 38
    Oliveira, T. A. D.; Silva, M. P. D.; Maia, E. H. B.; Silva, A. M. D.; Taranto, A. G. Virtual screening algorithms in drug discovery: a review focused on machine and deep learning methods. Drugs Drug Candidates. 2023, 2, 311– 334,  DOI: 10.3390/ddc2020017
    Google Scholar
    There is no corresponding record for this reference.
  39. 39
    Thongdee, P.; Hanwarinroj, C.; Pakamwong, B.; Kamsri, P.; Punkvang, A.; Leanpolchareanchai, J.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Ariyachaokun, K.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Mukamolova, G. V.; Blood, R. A.; Takebayashi, Y.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Virtual screening identifies novel and potent inhibitors of Mycobacterium tuberculosis PknB with antibacterial activity. J. Chem. Inf Model. 2022, 62, 6508– 6518,  DOI: 10.1021/acs.jcim.2c00531
    Google Scholar
    There is no corresponding record for this reference.
  40. 40
    Arica Sosa, A.; Alcántara, R.; Jiménez Avalos, G.; Zimic, M.; Milón, P.; Quiliano, M. Identifying RO9021 as a potential inhibitor of PknG from Mycobacterium tuberculosis: combinative computational and in vitro studies. ACS Omega. 2022, 7, 20204– 20218,  DOI: 10.1021/acsomega.2c02093
    Google Scholar
    There is no corresponding record for this reference.
  41. 41
    41. Sheikh, B. A.; Bhat, B. A.; Rizvi, M. A.; Ahmad, Z.; Almilaibary, A.; Alkhanani, M.; Mir, M. A. Computational studies to identify potential inhibitors targeting the DprE1 protein in Mycobacterium tuberculosis. Int. J. Pharm. Investig. 2023, 13, 129– 138,  DOI: 10.5530/223097131750
    Google Scholar
    There is no corresponding record for this reference.
  42. 42
    Verma, A.; Kumar, V.; Naik, B.; Khan, J. M.; Singh, P.; Saris, P. E. J.; Gupta, S. Screening and molecular dynamics simulation of compounds inhibiting MurB enzyme of drug–resistant Mycobacterium tuberculosis: An in–silico approach. Saudi J. Biol. Sci. 2023, 30, 103730  DOI: 10.1016/j.sjbs.2023.103730
    Google Scholar
    There is no corresponding record for this reference.
  43. 43
    Kumar, G. S.; Dubey, A.; Panda, S. P.; Alawi, M. M.; Sindi, A. A.; Azhar, E. I.; Dwivedi, V. D.; Agrawal, S. Repurposing of antibacterial compounds for suppression of Mycobacterium tuberculosis dormancy reactivation by targeting resuscitation–promoting factors B. J. Biomol. Struct. Dyn. 2023, 1– 13,  DOI: 10.1080/07391102.2023.2245059
    Google Scholar
    There is no corresponding record for this reference.
  44. 44
    Johannsen, S.; Gierse, R. M.; Olshanova, A.; Smerznak, E.; Laggner, C.; Eschweiler, L.; Adeli, Z.; Hamid, R.; Alhayek, A.; Reiling, N.; Haupenthal, J.; Hirsch, A. K. H. Not every hit–identification technique works on 1–deoxy–d–xylulose 5–phosphate synthase (DXPS): making the most of a virtual screening campaign. ChemMedChem 2023, 18, e202200590  DOI: 10.1002/cmdc.202200590
    Google Scholar
    There is no corresponding record for this reference.
  45. 45
    Damera, T.; Kondaparthi, V.; Bingi, M.; Mustyala, K. K.; Malkhed, V. Identification of novel scaffolds to inhibit Mycobacterium tuberculosis PimA protein–A computational approach. J. Cell Biochem. 2023, 124, 836– 848,  DOI: 10.1002/jcb.30412
    Google Scholar
    There is no corresponding record for this reference.
  46. 46
    Varon, H. A.; Santos, P.; Lopez-Vallejo, F.; Soto, C. Y. Novel scaffolds targeting Mycobacterium tuberculosis plasma membrane Ca2+ transporter CtpF by structure–based strategy. Bioorg. Chem. 2023, 138, 106648  DOI: 10.1016/j.bioorg.2023.106648
    Google Scholar
    There is no corresponding record for this reference.
  47. 47
    Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug–likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717,  DOI: 10.1038/srep42717
    Google Scholar
    47
    SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules
    Daina Antoine; Michielin Olivier; Zoete Vincent; Michielin Olivier; Michielin Olivier
    Scientific reports (2017), 7 (), 42717 ISSN:.
    To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
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  48. 48
    Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B. A.; Thiessen, P. A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E. E. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021, 49, D1388– D1395,  DOI: 10.1093/nar/gkaa971
    Google Scholar
    48
    PubChem in 2021: new data content and improved web interfaces
    Kim, Sunghwan; Chen, Jie; Cheng, Tiejun; Gindulyte, Asta; He, Jia; He, Siqian; Li, Qingliang; Shoemaker, Benjamin A.; Thiessen, Paul A.; Yu, Bo; Zaslavsky, Leonid; Zhang, Jian; Bolton, Evan E.
    Nucleic Acids Research (2021), 49 (D1), D1388-D1395CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    PubChem is a popular chem. information resource that serves the scientific community as well as the general public, with millions of unique users per mo. In the past 2 yr, PubChem made substantial improvements. Data from >100 new data sources were added to PubChem, including chem.-literature links from Thieme Chem., chem. and phys. property links from SpringerMaterials, and patent links from the World Intellectual Properties Organization (WIPO). PubChem's homepage and individual record pages were updated to help users find desired information faster. This update involved a data model change for the data objects used by these pages as well as by programmatic users. Several new services were introduced, including the PubChem Periodic Table and Element pages, Pathway pages, and Knowledge panels. Addnl., in response to the coronavirus disease 2019 (COVID-19) outbreak, PubChem created a special data collection that contains PubChem data related to COVID-19 and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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  49. 49
    Backman, T. W. H.; Cao, Y.; Girke, T. ChemMine tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res. 2011, 39, W486– W491,  DOI: 10.1093/nar/gkr320
    Google Scholar
    49
    ChemMine tools: an online service for analyzing and clustering small molecules
    Backman, Tyler W. H.; Cao, Yiqun; Girke, Thomas
    Nucleic Acids Research (2011), 39 (Web Server), W486-W491CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    ChemMine Tools is an online service for small mol. data anal. It provides a web interface to a set of chemoinformatics and data mining tools that are useful for various anal. routines performed in chem. genomics and drug discovery. The service also offers programmable access options via the R library ChemmineR. The primary functionalities of ChemMine Tools fall into five major application areas: data visualization, structure comparisons, similarity searching, compd. clustering and prediction of chem. properties. First, users can upload compd. data sets to the online Compd. Workbench. Numerous utilities are provided for compd. viewing, structure drawing and format interconversion. Second, pairwise structural similarities among compds. can be quantified. Third, interfaces to ultra-fast structure similarity search algorithms are available to efficiently mine the chem. space in the public domain. These include fingerprint and embedding/indexing algorithms. Fourth, the service includes a Clustering Toolbox that integrates chemoinformatic algorithms with data mining utilities to enable systematic structure and activity based analyses of custom compd. sets. Fifth, physicochem. property descriptors of custom compd. sets can be calcd. These descriptors are important for assessing the bioactivity profile of compds. in silico and quant. structure-activity relationship (QSAR) analyses. ChemMine Tools is available at: http://chemmine.ucr.edu.
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  50. 50
    Studier, F. W.; Moffatt, B. A. Use of bacteriophage T7 RNA polymerase to direct selective high–level expression of cloned genes. J. Mol. Biol. 1986, 189, 113– 130,  DOI: 10.1016/0022-2836(86)90385-2
    Google Scholar
    50
    Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes
    Studier, F. William; Moffatt, Barbara A.
    Journal of Molecular Biology (1986), 189 (1), 113-30CODEN: JMOBAK; ISSN:0022-2836.
    A gene expression system based on phage T7 RNA polymerase [9014-24-8] was developed. T7 RNA polymerase is highly selective for its own promoters, which do not occur naturally in Escherichia coli. A relatively small amt. of T7 RNA polymerase provided from a cloned copy of T7 gene 1 is sufficient to direct high-level transcription from a T7 promoter in a multicopy plasmid. Such transcription can proceed several times around the plasmid without terminating and can be so active that transcription by E. coli RNA polymerase is greatly decreased. When a cleavage site for RNase III is introduced, discrete RNAs of plasmid length can accumulate. The natural transcription terminator from T7 DNA also works effectively in the plasmid. Both the rate of synthesis and the accumulation of RNA directed by T7 RNA polymerase can reach levels comparable with those for rRNAs in a normal cell. These high levels of accumulation suggest that the RNAs are relatively stable, perhaps in part because their great length and(or) stem-and-loop structures at their 3' ends help to protect them against exonucleolytic degrdn. Apparently, a specific mRNA produced by T7 RNA polymerase can rapidly sat. the translational machinery of E. coli, so that the rate of protein synthesis from such an mRNA will depend primarily on the efficiency of its translation. When the mRNA is efficiently translated, a target protein can accumulate to >50% of the total cell protein in ≤3 h. Two ways were used to deliver active T7 RNA polymerase to the cell: (1) infection by a λ deriv. that carried gene 1; or (2) induction of a chromosomal copy of gene 1 under control of the lacUV5 promoter. When gene 1 is delivered by infection, very toxic target genes can be maintained silently in the cell until T7 RNA polymerase is introduced, when they rapidly become expressed at high levels. When gene 1 is resident in the chromosome, even the very low basal levels of T7 RNA polymerase present in the uninduced cell can prevent the establishment of plasmids carrying toxic target genes, or make the plasmid unstable. But if the target plasmid can be maintained, induction of chromosomal gene 1 can be a convenient way to produce large amts. of target RNA and(or) protein. T7 RNA polymerase seems to be capable of transcribing almost any DNA linked to a T7 promoter, so the T7 expression system should be capable of transcribing almost any gene or its complement in E. coli. Comparable T7 expression systems can be developed in other types of cells.
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  51. 51
    Laemmli, U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970, 227, 680– 685,  DOI: 10.1038/227680a0
    Google Scholar
    51
    Cleavage of structural proteins during the assembly of the head of bacteriophage T4
    Laemmli, U. K.
    Nature (London, United Kingdom) (1970), 227 (5259), 680-685CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Using an improved method of polyacrylamide gel electrophoresis based on the capability of SDS to break down proteins into their individual polypeptide chains, many previously unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products. Four major components of the head are cleaved during the process of assembly, apparently after the precursor proteins have assembled into some large intermediate structure.
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  52. 52
    Wang, X. D.; Meng, M. X.; Gao, L. B.; Liu, T.; Xu, Q.; Zeng, S. Permeation of astilbin and taxifolin in Caco–2 cell and their effects on the P–gp. Int. J. Pharm. 2009, 378, 1– 8,  DOI: 10.1016/j.ijpharm.2009.05.022
    Google Scholar
    52
    Permeation of astilbin and taxifolin in Caco-2 cell and their effects on the P-gp
    Wang, Xiao-dan; Meng, Min-xin; Gao, Ling-bo; Liu, Ting; Xu, Qiang; Zeng, Su
    International Journal of Pharmaceutics (2009), 378 (1-2), 1-8CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    This study was designed to understand the transport profiles of astilbin and taxifolin in Caco-2 cell model and their effects on the function and expression of P-glycoprotein. The transport studies were examd. using Caco-2 cells cultured on Transwell inserts. Their effects on the function and expression of P-glycoprotein were detected using Western Blot and RT-PCR. The transport was concn. and temp. dependent. The apparent permeability (P app) of these two compds. in the secretory direction was larger than that in the absorptive direction in the concn. range of 10-1000 μM. Those compds. had no effects on the P-glycoprotein-mediated transport of Rhodamine 123. Caco-2 cells exposed to astilbin or taxifolin for 36 h exhibited higher P-glycoprotein activity through up-regulating P-glycoprotein expression at protein and mRNA levels. These results indicated that P-glycoprotein and Multidrug Resistance Protein 2 might play important roles in limiting the bioavailability of those compds. Drugs which are the inhibitors of P-glycoprotein or Multidrug Resistance Protein 2 may increase the oral bioavailability of astilbin or taxifolin and the possibility of unwanted drug-food interactions. The increased expression of P-glycoprotein in Caco-2 cells may serve as an adaptation and defense mechanism in limiting the entry of xenobiotics into the body.
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  53. 53
    Faralli, A.; Shekarforoush, E.; Ajalloueian, F.; Mendes, A. C.; Chronakis, I. S. In vitro permeability enhancement of curcumin across Caco–2 cells monolayers using electrospun xanthan–chitosan nanofibers. Carbohydr. Polym. 2019, 206, 38– 47,  DOI: 10.1016/j.carbpol.2018.10.073
    Google Scholar
    There is no corresponding record for this reference.
  54. 54
    Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessmen of docking accuracy. J. Med. Chem. 2004, 47, 1739– 1749,  DOI: 10.1021/jm0306430
    Google Scholar
    54
    Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
    Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
    Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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  55. 55
    Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra Precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J. Med. Chem. 2006, 49, 6177– 6196,  DOI: 10.1021/jm051256o
    Google Scholar
    55
    Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
    Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.; Frye, Leah L.; Greenwood, Jeremy R.; Halgren, Thomas A.; Sanschagrin, Paul C.; Mainz, Daniel T.
    Journal of Medicinal Chemistry (2006), 49 (21), 6177-6196CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A novel scoring function to est. protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addn. to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included:(1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce exptl. binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, resp.) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP mol. recognition and water scoring in sepg. active and inactive ligands and avoiding false positives.
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  56. 56
    Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 2004, 47, 1750– 1759,  DOI: 10.1021/jm030644s
    Google Scholar
    56
    Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
    Halgren, Thomas A.; Murphy, Robert B.; Friesner, Richard A.; Beard, Hege S.; Frye, Leah L.; Pollard, W. Thomas; Banks, Jay L.
    Journal of Medicinal Chemistry (2004), 47 (7), 1750-1759CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Glide's ability to identify active compds. in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compd. collection of a pharmaceutical or biotechnol. company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that av. measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of phys. chem., particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
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  57. 57
    Petrella, S.; Capton, E.; Raynal, B.; Giffard, C.; Thureau, A.; Bonneté, F.; Alzari, P. M.; Aubry, A.; Mayer, C. Overall Structures of Mycobacterium tuberculosis DNA Gyrase Reveal the Role of a Corynebacteriales GyrB-Specific Insert in ATPase Activity. Structure. 2019, 27, 579– 589,  DOI: 10.1016/j.str.2019.01.004
    Google Scholar
    57
    Overall Structures of Mycobacterium tuberculosis DNA Gyrase Reveal the Role of a Corynebacteriales GyrB-Specific Insert in ATPase Activity
    Petrella, Stephanie; Capton, Estelle; Raynal, Bertrand; Giffard, Clement; Thureau, Aurelien; Bonnete, Francoise; Alzari, Pedro M.; Aubry, Alexandra; Mayer, Claudine
    Structure (Oxford, United Kingdom) (2019), 27 (4), 579-589.e5CODEN: STRUE6; ISSN:0969-2126. (Elsevier Ltd.)
    Despite sharing common features, previous studies have shown that gyrases from different species have been modified throughout evolution to modulate their properties. Here, we report two crystal structures of Mycobacterium tuberculosis DNA gyrase, an apo and AMPPNP-bound form at 2.6-Å and 3.3-Å resoln., resp. These structures provide high-resoln. structural data on the quaternary organization and interdomain connections of a gyrase (full-length GyrB-GyrA57)2 thus providing crucial inputs on this essential drug target. Together with small-angle X-ray scattering studies, they revealed an "extremely open" N-gate state, which persists even in the DNA-free gyrase-AMPPNP complex and an unexpected connection between the ATPase and cleavage core domains mediated by two Corynebacteriales-specific motifs, resp. the C-loop and DEEE-loop. We show that the C-loop participates in the stabilization of this open conformation, explaining why this gyrase has a lower ATPase activity. Our results image a conformational state which might be targeted for drug discovery.
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  58. 58
    Agrawal, A.; Roue, M.; Spitzfaden, C.; Petrella, S.; Aubry, A.; Hann, M.; Bax, B.; Mayer, C. Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion. Biochem. J. 2013, 456, 263– 273,  DOI: 10.1042/BJ20130538
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    58
    Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion
    Agrawal, Alka; Roue, Melanie; Spitzfaden, Claus; Petrella, Stephanie; Aubry, Alexandra; Hann, Michael; Bax, Benjamin; Mayer, Claudine
    Biochemical Journal (2013), 456 (2), 263-273CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
    DNA gyrase, a type II topoisomerase, regulates DNA topol. by creating a double-stranded break in one DNA duplex and transporting another DNA duplex [T-DNA (transported DNA)] through this break. The ATPase domains dimerize, in the presence of ATP, to trap the T-DNA segment. Hydrolysis of only one of the two ATPs, and release of the resulting Pi, is ratelimiting in DNA strand passage. A long unresolved puzzle is how the non-hydrolysable ATP analog AMP-PNP (adenosine 5'-[β,γ-imido]triphosphate) can catalyze one round of DNA strand passage without Pi release. In the present paper we discuss two crystal structures of the Mycobacterium tuberculosis DNA gyrase ATPase domain: one complexed with AMP-PCP (adenosine 5'-[β,γ-methylene]triphosphate) was unexpectedly monomeric, the other, an AMP-PNP complex, crystd. as a dimer. In the AMP-PNP structure, the unprotonated nitrogen (P-N=P imino) accepts hydrogen bonds from a well-ordered 'ATP lid', which is known to be required for dimerization. The equivalent CH2 group, in AMP-PCP, cannot accept hydrogen bonds, leaving the 'ATP lid' region disordered. Further anal. suggested that AMP-PNP can be converted from the imino (P-N=P) form into the imido form (P-NH-P) during the catalytic cycle. A main-chain NH is proposed to move to either protonate AMP-P-N=P to AMP-P-NH-P, or to protonate ATP to initiate ATP hydrolysis. This suggests a novel dissociative mechanism for ATP hydrolysis that could be applicable not only to GHKL phosphotransferases, but also to unrelated ATPases and GTPases such as Ras. On the basis of the domain orientation in our AMP-PCP structure we propose a mechanochem. scheme to explain how ATP hydrolysis is coupled to domain motion.
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  59. 59
    Shirude, P. S.; Madhavapeddi, P.; Tucker, J. A.; Murugan, K.; Patil, V.; Basavarajappa, H.; Raichurkar, A. V.; Humnabadkar, V.; Hussein, S.; Sharma, S.; Ramya, V. K.; Narayan, C. B.; Balganesh, T. S.; Sambandamurthy, V. K. Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis. ACS Chem. Biol. 2013, 8, 519– 523,  DOI: 10.1021/cb300510w
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    59
    Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis
    Shirude, Pravin S.; Madhavapeddi, Prashanti; Tucker, Julie A.; Murugan, Kannan; Patil, Vikas; Basavarajappa, Halesha; Raichurkar, Anandkumar V.; Humnabadkar, Vaishali; Hussein, Syeed; Sharma, Sreevalli; Ramya, V. K.; Narayan, Chandan B.; Balganesh, Tanjore S.; Sambandamurthy, Vasan K.
    ACS Chemical Biology (2013), 8 (3), 519-523CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chem. tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.
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  60. 60
    Greenwood, J. R.; Calkins, D.; Sullivan, A. P.; Shelley, J. C. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug–like molecules in aqueous solution. J. Comput. Aided Mol. Des. 2010, 24, 591– 604,  DOI: 10.1007/s10822-010-9349-1
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    60
    Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution
    Greenwood, Jeremy R.; Calkins, David; Sullivan, Arron P.; Shelley, John C.
    Journal of Computer-Aided Molecular Design (2010), 24 (6-7), 591-604CODEN: JCADEQ; ISSN:0920-654X. (Springer)
    A review. Generating the appropriate protonation states of drug-like mols. in soln. is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compds. requires a method for detg. tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximize enrichment, the lowest energy tautomers must be detd. from heterogeneous input, without over-enumerating unfavorable states. While computationally expensive, the d. functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett-Taft methodol. can very rapidly extrapolate substituent effects from model systems to drug-like mols. via the relationship between pKT and pKa. Combining the 2 complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited no. of measured pKT values, esp. for the complicated heterocycles often favored by medicinal chemists for their novelty and versatility. Several hundreds of pre-calcd. tautomer energies and substituent pKa effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aq. ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and exptl. data. Recommendations are made for how to best incorporate tautomers in mol. design and virtual screening workflows.
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  61. 61
    Shelley, J. C.; Cholleti, A.; Frye, L. L.; Greenwood, J. R.; Timlin, M. R.; Uchimaya, M. Epik: a software program for pKa prediction and protonation state generation for drug–like molecules. J. Comput. Aided Mol. Des. 2007, 21, 681– 691,  DOI: 10.1007/s10822-007-9133-z
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    61
    Epik: a software program for pKa prediction and protonation state generation for drug-like molecules
    Shelley, John C.; Cholleti, Anuradha; Frye, Leah L.; Greenwood, Jeremy R.; Timlin, Mathew R.; Uchimaya, Makoto
    Journal of Computer-Aided Molecular Design (2007), 21 (12), 681-691CODEN: JCADEQ; ISSN:0920-654X. (Springer)
    Epik is a computer program for predicting pKa values for drug-like mols. Epik can use this capability in combination with technol. for tautomerization to adjust the protonation state of small drug-like mols. to automatically generate one or more of the most probable forms for use in further mol. modeling studies. Many medicinal chems. can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its soly. and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the mol., as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate mols. used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like mols. to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the mol. itself rather just for the particular Lewis structure used on input. In addn., a new iterative technol. for generating, ranking and culling the generated protonation states is employed.
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  62. 62
    Case, D. A.; Aktulga, H. M.; Belfon, K.; Ben Shalom, I. Y.; Brozell, S. R.; Cerutti, D. S.; Cheatham, III, T. E.; Cisneros, G. A.; Cruzeiro, V. W. D.; Darden, T. A.; Duke, R. E.; Giambasu, G.; Gilson, M. K.; Gohlke, H.; Goetz, A. W.; Harris, R.; Izadi, S.; Izmailov, S. A.; Jin, C.; Kasavajhala, K.; Kaymak, M. C.; King, E.; Kovalenko, A.; Kurtzman, T.; Lee, T. S.; LeGrand, S.; Li, P.; Lin, C.; Liu, J.; Luchko, T.; Luo, R.; Machado, M.; Man, V.; Manathunga, M.; Merz, K. M.; Miao, Y.; Mikhailovskii, O.; Monard, G.; Nguyen, H.; O’Hearn, K. A.; Onufriev, A.; Pan, F.; Pantano, S.; Qi, R.; Rahnamoun, A.; Roe, D. R.; Roitberg, A.; Sagui, C.; Schott Verdugo, S.; Shen, J.; Simmerling, C. L.; Skrynnikov, N. R.; Smith, J.; Swails, J.; Walker, R. C.; Wang, J.; Wei, H.; Wolf, R. M.; Wu, X.; Xue, Y.; York, D. M.; Zhao, S.; Kollman, P. A. Amber 2020; University of California: San Francisco, 2021.
    Google Scholar
    There is no corresponding record for this reference.
  63. 63
    Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 2004, 25, 1157– 1174,  DOI: 10.1002/jcc.20035
    Google Scholar
    63
    Development and testing of a general Amber force field
    Wang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.
    Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
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  64. 64
    Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A Well behaved electrostatic potential based method using charge restraints for deriving atomic charges: The RESP model. J. Phys. Chem. 1993, 97, 10269– 10280,  DOI: 10.1021/j100142a004
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    64
    A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model
    Bayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy; Kollman, Peter A.
    Journal of Physical Chemistry (1993), 97 (40), 10269-80CODEN: JPCHAX; ISSN:0022-3654.
    The authors present a new approach to generating electrostatic potential (ESP) derived charges for mols. The major strength of electrostatic potential derived charges is that they optimally reproduce the intermol. interaction properties of mols. with a simple two-body additive potential, provided, of course, that a suitably accurate level of quantum mech. calcn. is used to derive the ESP around the mol. Previously, the major weaknesses of these charges have been that they were not easily transferably between common functional groups in related mols., they have often been conformationally dependent, and the large charges that frequently occur can be problematic for simulating intramol. interactions. Introducing restraints in the form of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the fit to the quantum mech. ESP. Several other refinements in addn. to the restrained electrostatic potential (RESP) fit yield a general and algorithmic charge fitting procedure for generating atom-centered point charges. This approach can thus be recommended for general use in mol. mechanics, mol. dynamics, and free energy calcns. for any org. or bioorg. system.
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  65. 65
    Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins. J. Comput. Chem. 1995, 16, 1357– 1377,  DOI: 10.1002/jcc.540161106
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    65
    Application of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteins
    Cieplak, Piotr; Cornell, Wendy D.; Bayly, Christopher; Kollman, Peter A.
    Journal of Computational Chemistry (1995), 16 (11), 1357-77CODEN: JCCHDD; ISSN:0192-8651. (Wiley)
    The authors present the derivation of charges of ribo- and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calcns. with the 6-31G* basis set. For the nucleic acid fragments, the authors used electrostatic potentials of the four deoxyribonucleoside (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-mol. fitting and restrained electrostatic potential (RESP) fits, with Lagrangian multipliers ensuring a net charge of 0 or. The authors suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1' and H1' of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equiv. For peptide fragments, the authors have combined multiple conformation fitting, previously employed by Williams and Reynolds et al., with the RESP approach to derive charges for blocked dipeptides appropriate for each of the 20 naturally occurring amino acids. Based on the results for Pr amine, the authors suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of mols., provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms or hydrogens attached to heteroatoms. In these blocked dipeptide models, it is useful to require equiv. N-H and C=O charges for all amino acids with a given net charge (except proline), and this is accomplished in a straightforward fashion with multiple-mol. fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chem. blocked version of the residue. The multiple Lagrange constraints also enable charges from two or more mols. to be spliced together in a well-defined fashion. Thus, the combined use of multiple mols., multiple conformations, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers.
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  66. 66
    Fox, T.; Kollman, P. A. Application of the RESP methodology in the parametrization of organic solvents. J. Phys. Chem. B 1998, 102, 8070– 8079,  DOI: 10.1021/jp9717655
    Google Scholar
    66
    Application of the RESP Methodology in the Parametrization of Organic Solvents
    Fox, Thomas; Kollman, Peter A.
    Journal of Physical Chemistry B (1998), 102 (41), 8070-8079CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
    We present parameterizations for the nonaq. solvents DMSO, ethanol, CCl4, CHCl3, and CH2Cl2 that are compatible with the recent AMBER force field by Cornell et al. (J. Am. Chem. Soc. 1995, 117, 5179-5197). With the general procedure for generating new parameters and the RESP approach to obtain the at. charges, we achieve flexible all-atom solvent models whose d., heat of vaporization, diffusion const., and rotational correlation times are-esp. for a generic force field-in good agreement with available exptl. data.
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  67. 67
    Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983, 79, 926– 935,  DOI: 10.1063/1.445869
    Google Scholar
    67
    Comparison of simple potential functions for simulating liquid water
    Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
    Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
    Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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  68. 68
    Roe, D. R.; Cheatham, T., III. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J. Chem. Theory Comput. 2013, 9, 3084– 3095,  DOI: 10.1021/ct400341p
    Google Scholar
    68
    PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
    Roe, Daniel R.; Cheatham, Thomas E.
    Journal of Chemical Theory and Computation (2013), 9 (7), 3084-3095CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the anal. and processing of time series of three-dimensional at. positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange mol. dynamics), image with periodic boundary conditions, create av. structures, strip subsets of the system, and perform calcns. such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
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  69. 69
    Wang, E.; Sun, H.; Wang, J.; Wang, Z.; Liu, H.; Zhang, J. Z. H.; Hou, T. End–point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design. Chem. Rev. 2019, 119, 9478– 9508,  DOI: 10.1021/acs.chemrev.9b00055
    Google Scholar
    There is no corresponding record for this reference.
  70. 70
    Hou, T.; Yu, R. Molecular dynamics and free energy studies on the wild–type and double mutant HIV–1 protease complexed with amprenavir and two amprenavir–related inhibitors: mechanism for binding and drug resistance. J. Med. Chem. 2007, 50, 1177– 1188,  DOI: 10.1021/jm0609162
    Google Scholar
    70
    Molecular Dynamics and Free Energy Studies on the Wild-type and Double Mutant HIV-1 Protease Complexed with Amprenavir and Two Amprenavir-Related Inhibitors: Mechanism for Binding and Drug Resistance
    Hou, Tingjun; Yu, Ron
    Journal of Medicinal Chemistry (2007), 50 (6), 1177-1188CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The V82F/I84V double mutation is considered as the key residue mutation of the HIV-1 protease drug resistance because it can significantly lower the binding affinity of protease inhibitors in clin. uses. In the current work, the binding of amprenavir to both of the wild-type and the drug-resistant V82F/I84V mutant of the HIV-1 protease was investigated by mol. dynamics (MD) simulations and was compared to those of two inhibitors in development, TMC126 and TMC114. Abs. binding free energies were calcd. by mol. mechanics/Poisson-Boltzmann surface area (MM/ PBSA) methodol. The predicted binding affinities give a good explanation of structure-affinity relation (SAR) of three studied inhibitors. Furthermore, in the 18 ns MD simulations on the free wild-type and the mutated proteases, we obsd. that the free mutated protease shows similar dynamic characteristics of the flap opening and a little higher structural stability than the free wild-type protease. This suggests that the effect of the mutations may not significantly affect the equil. between the semi-open and the closed conformations. Finally, decompn. anal. of binding free energies and the further structural anal. indicate that the dominating effect of the V82F/I84V double mutation is to distort the geometry of the binding site and hence weaken the interactions of inhibitors pre-shaped to the wild-type binding site.
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  71. 71
    Li, W.; Zhang, J.; Guo, L.; Wang, Q. Importance of three–body problems and protein–protein interactions in proteolysis–targeting chimera modeling: Insights from molecular dynamics simulations. J. Chem. Inf. Model. 2022, 62, 523– 532,  DOI: 10.1021/acs.jcim.1c01150
    Google Scholar
    There is no corresponding record for this reference.
  72. 72
    Miller, B. R.; McGee, T. D.; Swails, J. M.; Homeyer, N.; Gohlke, H.; Roitberg, A. E. MMPBSA.py: An efficient program for end–state free energy calculations. J. Chem. Theory Comput. 2012, 8, 3314– 3321,  DOI: 10.1021/ct300418h
    Google Scholar
    72
    MMPBSA.py: An Efficient Program for End-State Free Energy Calculations
    Miller, Bill R., III; McGee, T. Dwight, Jr.; Swails, Jason M.; Homeyer, Nadine; Gohlke, Holger; Roitberg, Adrian E.
    Journal of Chemical Theory and Computation (2012), 8 (9), 3314-3321CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    MM-PBSA is a post-processing end-state method to calc. free energies of mols. in soln. MMPBSA.py is a program written in Python for streamlining end-state free energy calcns. using ensembles derived from mol. dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Ref. Interaction Site Model. Vibrational frequencies may be calcd. using normal mode or quasi-harmonic anal. to approx. the solute entropy. Specific interactions can also be dissected using free energy decompn. or alanine scanning. A parallel implementation significantly speeds up the calcn. by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calcns. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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  73. 73
    Onufriev, A.; Bashford, D.; Case, D. A. Exploring protein native states and large–scale conformational changes with a modified generalized born model. Proteins. 2004, 55, 383– 394,  DOI: 10.1002/prot.20033
    Google Scholar
    73
    Exploring protein native states and large-scale conformational changes with a modified Generalized Born model
    Onufriev, Alexey; Bashford, Donald; Case, David A.
    Proteins: Structure, Function, and Bioinformatics (2004), 55 (2), 383-394CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)
    Implicit solvation models provide, for many applications, a reasonably accurate and computationally effective way to describe the electrostatics of aq. solvation. Here, a popular anal. Generalized Born (GB) solvation model is modified to improve its accuracy in calcg. the solvent polarization part of free energy changes in large-scale conformational transitions, such as protein folding. In contrast to an earlier GB model (implemented in the AMBER-6 program), the improved version does not overstabilize the native structures relative to the finite-difference Poisson-Boltzmann continuum treatment. In addn. to improving the energy balance between folded and unfolded conformers, the algorithm (available in the AMBER-7 and NAB mol. modeling packages) is shown to perform well in more than 50 ns of native-state mol. dynamics (MD) simulations of thioredoxin, protein-A, and ubiquitin, as well as in a simulation of Barnase/Barstar complex formation. For thioredoxin, various combinations of input parameters have been explored, such as the underlying gas-phase force fields and the at. radii. The best performance is achieved with a previously proposed modification to the torsional potential in the Amber ff99 force field, which yields stable native trajectories for all of the tested proteins, with back-bone root-mean-square deviations from the native structures being ∼ 1.5 Å after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 Å relative to the crystal structure of the complex.
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  74. 74
    Weiser, J.; Shenkin, P. S.; Still, W. C. Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J. Comput. Chem. 1999, 20, 217– 230,  DOI: 10.1002/(SICI)1096-987X(19990130)20:2<217::AID-JCC4>3.0.CO;2-A
    Google Scholar
    74
    Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)
    Weiser, Jorg; Shenkin, Peter S.; Still, W. Clark
    Journal of Computational Chemistry (1999), 20 (2), 217-230CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    A fast anal. formula was derived for the calcn. of approx. at. and mol. van der Waals (vdWSA), and solvent-accessible surface areas (SASAs), as well as the first and second derivs. of these quantities with respect to at. coordinates. This method makes use of linear combinations of terms composed from pairwise overlaps of hard spheres; therefore, we term this the LCPO method for linear combination of pairwise overlaps. For higher performance, neighbor-list redn. (NLR) was applied as a preprocessing step. Eighteen compds. of different sizes (8-2366 atoms) and classes (org., proteins, DNA, and various complexes) were chosen as representative test cases. LCPO/NLR computed the SASA and first derivs. of penicillopepsin, a protein with 2366 atoms, in 0.87 s (0.22 s for the creation of the neighbor list, 0.35 s for NLR, and 0.30 s for SASA and first derivs.) on an SGI R10000/194 Mhz processor. This appears comparable to or better than timings reported previously for other algorithms. The vdWSAs were in good agreement with the numerical results: relative errors for total mol. surface areas ranged from 0.1 to 2.0% and av. abs. at. surface area deviations from 0.3 to 0.7 Å2. For SASAs without NLR, the LCPO method exhibited relative errors in the range of 0.4-9.2% for total mol. surface areas and av. abs. at. surface area deviations of 2.0-2.7 Å2; with NLR the relative mol. errors ranged from 0.1 to 7.8% and the av. abs. at. surface area deviation from 1.6 to 3.0 Å2.
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  75. 75
    Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2001, 46, 3– 26,  DOI: 10.1016/S0169-409X(00)00129-0
    Google Scholar
    75
    Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
    Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
    Advanced Drug Delivery Reviews (2001), 46 (1-3), 3-26CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
    A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is greater than 500 and the calcd. Log P (CLogP) is greater than 5 (or MlogP >4.15). Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
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  76. 76
    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
    Google Scholar
    76
    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.
    >> More from SciFinder ®
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  77. 77
    Alt, S.; Mitchenall, L. A.; Maxwell, A.; Heide, L. Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. J. Antimicrob. Chemother. 2011, 66, 2061– 2069,  DOI: 10.1093/jac/dkr247
    Google Scholar
    77
    Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics
    Alt, Silke; Mitchenall, Lesley A.; Maxwell, Anthony; Heide, Lutz
    Journal of Antimicrobial Chemotherapy (2011), 66 (9), 2061-2069CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    Aminocoumarin antibiotics are potent inhibitors of bacterial DNA gyrase. We investigated the inhibitory and antibacterial activity of naturally occurring aminocoumarin antibiotics and six structural analogs (novclobiocins) against DNA gyrase and DNA topoisomerase IV from Escherichia coli and Staphylococcus aureus as well as the effect of potassium and sodium glutamate on the activity of these enzymes. The inhibitory concns. of the aminocoumarins were detd. in gyrase supercoiling assays and topoisomerase IV decatenation assays. Both subunits of S. aureus topoisomerase IV were purified as His-Tag proteins in E. coli. The MIC was tested in vivo for the control organisms E. coli ATCC 25922 and S. aureus ATCC 29213. DNA gyrase is the primary target in vitro of all investigated aminocoumarins. With the exception of simocyclinone D8, all other aminocoumarins inhibited S. aureus gyrase on av. 6-fold more effectively than E. coli gyrase. Potassium glutamate is essential for the activity of S. aureus gyrase and increases the sensitivity of E. coli gyrase to aminocoumarins ≥10-fold. The antibacterial activity of the tested compds. mirrored their relative activities against topoisomerases. The study provides insights about the substituents that are important for the inhibitory activity of aminocoumarins against the target enzymes, which will facilitate the rational design of improved antibiotics.
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  78. 78
    Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS. Infect. Dis. 2015, 1, 4– 41,  DOI: 10.1021/id500013t
    Google Scholar
    There is no corresponding record for this reference.
  79. 79
    Duma, R. J.; Warner, J. F. In Vitro Activity of Coumermycin A1 Against Mycobacterium tuberculosis var. hominis. Appl. Microbiol. 1969, 18, 404– 405,  DOI: 10.1128/am.18.3.404-405.1969
    Google Scholar
    There is no corresponding record for this reference.
  80. 80
    Broeck, A. V.; McEwen, A. G.; Chebaro, Y.; Potier, N.; Lamour, V. Structural Basis for DNA Gyrase Interaction with Coumermycin A1. J. Med. Chem. 2019, 62, 4225– 4231,  DOI: 10.1021/acs.jmedchem.8b01928
    Google Scholar
    There is no corresponding record for this reference.
  81. 81
    Gl, B.; Rajput, R.; Gupta, M.; Dahiya, P.; Thakur, J. K.; Bhatnagar, R.; Grover, A. Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis. Biochem. J. 2020, 477, 4167– 4190,  DOI: 10.1042/BCJ20200462
    Google Scholar
    81
    Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
    Gl Balasubramani; Rajput Rinky; Grover Abhinav; Gupta Manish; Bhatnagar Rakesh; Dahiya Pradeep; Thakur Jitendra K; Bhatnagar Rakesh
    The Biochemical journal (2020), 477 (21), 4167-4190 ISSN:.
    Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening the drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a potent binder of MtbGyrB47. Furthermore, ATPase, and DNA supercoiling assays exhibited an IC50 values of 2.1-4.7 μM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 and 12 μM were observed for epirubicin and echinacoside, respectively, against Mtb. Our findings indicate that echinacoside and epirubicin targets mycobacterial DNA gyrase, inhibit its catalytic cycle, and retard mycobacterium growth. Further, these compounds exhibit potential scaffolds for optimizing novel anti-mycobacterial agents that can act on drug-resistant strains.
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  82. 82
    Sherer, B. A.; Hull, K.; Green, O.; Basarab, G.; Hauck, S.; Hill, P.; Loch, J. T., 3rd.; Mullen, G.; Bist, S.; Bryant, J.; Boriack-Sjodin, A.; Read, J.; DeGrace, N.; Uria-Nickelsen, M.; Illingworth, R. N.; Eakin, A. E. Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy. Bioorg. Med. Chem. Lett. 2011, 21, 7416– 7420,  DOI: 10.1016/j.bmcl.2011.10.010
    Google Scholar
    82
    Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy
    Sherer, Brian A.; Hull, Kenneth; Green, Oluyinka; Basarab, Gregory; Hauck, Sheila; Hill, Pamela; Loch, James T., III; Mullen, George; Bist, Shanta; Bryant, Joanna; Boriack-Sjodin, Ann; Read, Jon; DeGrace, Nancy; Uria-Nickelsen, Maria; Illingworth, Ruth N.; Eakin, Ann E.
    Bioorganic & Medicinal Chemistry Letters (2011), 21 (24), 7416-7420CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochem. activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the mol. resulted in pyrrolamides with improved cellular activity and in vivo efficacy.
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  83. 83
    Durcik, M.; Nyerges, Á.; Skok, Ž.; Skledar, D. G.; Trontelj, J.; Zidar, N.; Ilaš, J.; Zega, A.; Cruz, C. D.; Tammela, P.; Welin, M.; Kimbung, Y. R.; Focht, D.; Benek, O.; Révész, T.; Draskovits, G.; Szili, PÉ; Daruka, L.; Pál, C.; Kikelj, D.; Mašič, L. P.; Tomašič, T. New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens. Eur. J. Med. Chem. 2021, 213, 113200  DOI: 10.1016/j.ejmech.2021.113200
    Google Scholar
    83
    New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens
    Durcik, Martina; Nyerges, Akos; Skok, Ziga; Skledar, Darja Gramec; Trontelj, Jurij; Zidar, Nace; Ilas, Janez; Zega, Anamarija; Cruz, Cristina D.; Tammela, Paivi; Welin, Martin; Kimbung, Yengo R.; Focht, Dorota; Benek, Ondrej; Revesz, Tamas; Draskovits, Gabor; Szili, Petra Eva; Daruka, Lejla; Pal, Csaba; Kikelj, Danijel; Masic, Lucija Peterlin; Tomasic, Tihomir
    European Journal of Medicinal Chemistry (2021), 213 (), 113200CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Here, the design and structure-activity relationship anal. of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens were reported. For inhibitor I•HCl (R = 2-(morpholin-4-yl)ethyl), a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compds. The best inhibitor, I [R = thiophen-3-yl-Me (II)], does not show any in vitro cytotoxicity and has excellent potency against Gram-pos. (MICs: range, 0.0078-0.0625μg/mL) and Gram-neg. pathogens (MICs: range, 1-2μg/mL). Furthermore, II inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, it was expected that structural derivs. of II will represent a step toward clin. efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.
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  84. 84
    Mesleh, M. F.; Cross, J. B.; Zhang, J.; Kahmann, J.; Andersen, O. A.; Barker, J.; Cheng, R. K.; Felicetti, B.; Wood, M.; Hadfield, A. T.; Scheich, C.; Moy, T. I.; Yang, Q.; Shotwell, J.; Nguyen, K.; Lippa, B.; Dolle, R.; Ryan, M. D. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Bioorg. Med. Chem. Lett. 2016, 26, 1314– 1318,  DOI: 10.1016/j.bmcl.2016.01.009
    Google Scholar
    There is no corresponding record for this reference.
  85. 85
    Ushiyama, F.; Amada, H.; Takeuchi, T.; Tanaka-Yamamoto, N.; Kanazawa, H.; Nakano, K.; Mima, M.; Masuko, A.; Takata, I.; Hitaka, K.; Iwamoto, K.; Sugiyama, H.; Ohtake, N. Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation. ACS Omega 2022, 5, 10145– 10159,  DOI: 10.1021/acsomega.0c00865
    Google Scholar
    There is no corresponding record for this reference.
  86. 86
    Skok, Ž.; Barančoková, M.; Benek, O.; Cruz, C. D.; Tammela, P.; Tomašič, T.; Zidar, N.; Mašič, L. P.; Zega, A.; Stevenson, C. E. M.; Mundy, J. E. A.; Lawson, D. M.; Maxwell, A.; Kikelj, D.; Ilaš, J. Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors. ACS Med. Chem. Lett. 2020, 11, 2433– 2440,  DOI: 10.1021/acsmedchemlett.0c00416
    Google Scholar
    86
    Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors
    Skok, Ziga; Barancokova, Michaela; Benek, Ondrej; Cruz, Cristina Durante; Tammela, Paivi; Tomasic, Tihomir; Zidar, Nace; Masic, Lucija Peterlin; Zega, Anamarija; Stevenson, Clare E. M.; Mundy, Julia E. A.; Lawson, David M.; Maxwell, Anthony; Kikelj, Danijel; Ilas, Janez
    ACS Medicinal Chemistry Letters (2020), 11 (12), 2433-2440CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymic activity, we systematically explored the chem. space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compds. with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compd. 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compd. 15a, with a low mol. wt. of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13μM), and efflux impaired E. coli strain (MIC = 0.78μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-neg. bacteria.
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  87. 87
    Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J. Med. Chem. 2012, 55, 6413– 6426,  DOI: 10.1021/jm300395d
    Google Scholar
    87
    Structure-Based Discovery of Substituted 4,5'-Bithiazoles as Novel DNA Gyrase Inhibitors
    Brvar, Matjaz; Perdih, Andrej; Renko, Miha; Anderluh, Gregor; Turk, Dusan; Solmajer, Tom
    Journal of Medicinal Chemistry (2012), 55 (14), 6413-6426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N2-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallog., confirming our initial in silico binding model. Furthermore, the high resoln. of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
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  88. 88
    Manchester, J. I.; Dussault, D. D.; Rose, J. A.; Boriack-Sjodin, P. A.; Uria-Nickelsen, M.; Ioannidis, G.; Bist, S.; Fleming, P.; Hull, K. G. Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV. Bioorg. Med. Chem. Lett. 2012, 22, 5150– 5156,  DOI: 10.1016/j.bmcl.2012.05.128
    Google Scholar
    88
    Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV
    Manchester, John I.; Dussault, Daemian D.; Rose, Jonathan A.; Boriack-Sjodin, P. Ann; Uria-Nickelsen, Maria; Ioannidis, Georgine; Bist, Shanta; Fleming, Paul; Hull, Kenneth G.
    Bioorganic & Medicinal Chemistry Letters (2012), 22 (15), 5150-5156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The discovery and optimization of a series of bacterial topoisomerase inhibitors, e.g., I, is disclosed. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and phys. property optimization. Synthesis of fewer than a dozen compds. was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus at compd. concns. of 1.56 μM. These compds. simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concns., reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.
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  89. 89
    Gross, C. H.; Parsons, J. D.; Grossman, T. H.; Charifson, P. S.; Bellon, S.; Jernee, J.; Dwyer, M.; Chambers, S. P.; Markland, W.; Botfield, M.; Raybuck, S. A. Active–site residues of Escherichia coli DNA gyrase required in coupling ATP hydrolysis to DNA supercoiling and amino acid substitutions leading to novobiocin resistance. Antimicrob. Agents Chemother. 2003, 47, 1037– 1046,  DOI: 10.1128/AAC.47.3.1037-1046.2003
    Google Scholar
    There is no corresponding record for this reference.

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  1. Iqball Faheem, Valakunja Nagaraja. Multifunctional Mycobacterial Topoisomerases with Distinctive Features. ACS Infectious Diseases 2025, Article ASAP.
  2. K. Rajakumari, K. Aravind, M. Balamugundhan, Manjunathan Jagadeesan, Ambiga Somasundaram, Parthiban Brindha Devi, Pasiyappazham Ramasamy. Comprehensive review of DNA gyrase as enzymatic target for drug discovery and development. European Journal of Medicinal Chemistry Reports 2024, 12 , 100233. https://doi.org/10.1016/j.ejmcr.2024.100233
  3. Balazs Balega, Michael Beer, James Spencer, Giorgio Colombo, Stefano A. Serapian, A. Sofia F. Oliveira, Adrian J. Mulholland. Dynamical nonequilibrium molecular dynamics simulations reveal allosteric networks, signal transduction mechanisms, and sites associated with drug resistance in biomolecular systems. Molecular Physics 2024, 6 https://doi.org/10.1080/00268976.2024.2428350
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  • Abstract

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    Figure 1

    Figure 1. Virtual screening workflow for discovery of M. tuberculosis DNA gyrase inhibitors.

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    Figure 2

    Figure 2. New hit compounds identified in this work. Structures of hit compounds (1–14), G24, and novobiocin together with Specs code, MIC against M. tuberculosis H37Ra, and IC50 for inhibition of M. tuberculosis DNA gyrase ATPase activity. ND indicates not determined.

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    Figure 3

    Figure 3. Inhibition of M. tuberculosis DNA gyrase ATPase activity. IC50 curves for inhibition of M. tuberculosis DNA gyrase ATPase activity by compounds 1, 2, 3, 8, 11, 14, G24, and novobiocin. IC50 values were obtained from nonlinear regression fitting of % inhibition to log of the inhibitor concentration. Error bars represent standard deviations (N = 3). Note that in some cases, these are obscured by symbols. Further details of fit parameters are given in Table S3.

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    Figure 4

    Figure 4. Superimpositions of AMP-PCP, indole derivatives G24, and compounds 8(R), 11(R), and 14(R) in the M. tuberculosis DNA gyrase ATP binding site. (A), (D), and (G) Superimpositions of previously described indole derivative (G24, R configuration, light pink stick) and compounds 8(R), 11(R), and 14(R) (cyan green, magenta, and pale yellow sticks) in the M. tuberculosis GyrB ATP binding site. Binding modes are predicted from MD simulations. (B), (E), and (H) Superimposition of AMP-PCP (PDB 3ZM7, (58) marine sticks) and compounds 8(R), 11(R), and 14(R) (cyan green, magenta, and pale yellow sticks, binding modes predicted from MD simulations). (C), (F), and (I) Hydrogen bond interactions (dashed red arrows) of compounds 8(R), 11(R), and 14(R) with Asp79.

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  • References

    This article references 89 other publications.

    1. 1
      WHO. Global tuberculosis report 2023. https://www.who.int/publications/i/item/9789240083851 (accessed January 2024).
      There is no corresponding record for this reference.
    2. 2
      Aubry, A.; Fisher, L. M.; Jarlier, V.; Cambau, E. First functional characterization of a singly expressed bacterial type II topoisomerase: the enzyme from Mycobacterium tuberculosis. Biochem. Biophys. Res. Commun. 2006, 348, 158– 165,  DOI: 10.1016/j.bbrc.2006.07.017
      2
      First functional characterization of a singly expressed bacterial type II topoisomerase: The enzyme from Mycobacterium tuberculosis
      Aubry, Alexandra; Mark Fisher, L.; Jarlier, Vincent; Cambau, Emmanuelle
      Biochemical and Biophysical Research Communications (2006), 348 (1), 158-165CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)
      Genome deciphering revealed that Mycobacterium tuberculosis encodes a single type II topoisomerase contrary to common bacteria harboring two type II topoisomerases (DNA gyrase and topoisomerase IV). Functions of the M. tuberculosis type II topoisomerase were explored after cloning and expressing the subunits encoding genes in Escherichia coli. M. tuberculosis type II topoisomerase supercoiled relaxed pBR322 with a specific activity close to that of DNA gyrases of common bacteria whereas it exhibited DNA relaxation and formation of cleavable complexes with activities significantly higher than other DNA gyrases. Intermol. passage activity evaluated by the decatenation of kinetoplast DNA was 25-fold lower than that of the topoisomerase IV from Streptococcus pneumoniae, but was markedly higher than that of the E. coli gyrase. Overall, the type II topoisomerase of M. tuberculosis exhibits classical polyvalent activities of DNA gyrase for supercoiling but enhanced relaxation, cleavage, and decatenation activities.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xot1Wqtbg%253D&md5=763bef9f46308f23af208f537e82c1bd
    3. 3
      Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E., 3rd; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M. A.; Rajandream, M. A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.; Taylor, K.; Whitehead, S.; Barrell, B. G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998, 393, 537– 544,  DOI: 10.1038/31159
      3
      Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
      Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E., III; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M. A.; Rajandream, M.-A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.; Taylor, K.; Whitehead, S.; Barrell, B. G.
      Nature (London) (1998), 393 (6685), 537-544CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
      Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, was detd. and analyzed in order to improve our understanding of the biol. of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4000 genes, and has a very high G+C content that is reflected in the biased amino acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the prodn. of enzymes involved in lipogenesis and lipolysis, and to 2 new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.
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    4. 4
      Bush, N. G.; Evans-Roberts, K.; Maxwell, A. DNA Topoisomerases. EcoSal Plus 2015, 6, 1– 34,  DOI: 10.1128/ecosalplus.esp-0010-2014
      There is no corresponding record for this reference.
    5. 5
      Asif, M.; Siddiqui, A. A.; Husain, A. Quinolone derivatives as antitubercular drugs. Med. Chem. Res. 2013, 22, 1029– 1042,  DOI: 10.1007/s00044-012-0101-3
      There is no corresponding record for this reference.
    6. 6
      Facchinetti, V.; Gomes, C. R. B.; de Souza, M. V. N.; Vasconcelos, T. R. A. Perspectives on the development of novel potentially active quinolones against tuberculosis and cancer. Mini-Rev. Med. Chem. 2012, 12, 866– 874,  DOI: 10.2174/138955712800959099
      There is no corresponding record for this reference.
    7. 7
      Kathrotiya, H. G.; Patel, M. P. Synthesis and identification of β–aryloxyquinoline based diversely fluorine substituted N–aryl quinolone derivatives as a new class of antimicrobial, antituberculosis and antioxidant agents. Eur. J. Med. Chem. 2013, 63, 675– 684,  DOI: 10.1016/j.ejmech.2013.03.017
      There is no corresponding record for this reference.
    8. 8
      Kim, O. K.; Ohemeng, K.; Barrett, J. F. Advances in DNA gyrase inhibitors. Expert Opin. Investig. Drugs. 2001, 10, 199– 212,  DOI: 10.1517/13543784.10.2.199
      There is no corresponding record for this reference.
    9. 9
      Liu, K. L.; Teng, F.; Xiong, L.; Li, X.; Gao, C.; Yu, L. T. Discovery of quinolone derivatives as antimycobacterial agents. RSC Adv. 2021, 11, 24095– 24115,  DOI: 10.1039/D0RA09250A
      There is no corresponding record for this reference.
    10. 10
      Sriram, D.; Aubry, A.; Yogeeswari, P.; Fisher, L. M. Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase. Bioorg. Med. Chem. Lett. 2006, 16, 2982– 2985,  DOI: 10.1016/j.bmcl.2006.02.065
      There is no corresponding record for this reference.
    11. 11
      Huang, T. S.; Kunin, C. M.; Lee, S. S. J.; Chen, Y. S.; Tu, H. Z.; Liu, Y. C. Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995–2003. J. Antimicrob. Chemother. 2005, 56, 1058– 1062,  DOI: 10.1093/jac/dki353
      11
      Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995-2003
      Huang, Tsi-Shu; Kunin, Calvin M.; Lee, Susan Shin-Jung; Chen, Yao-Shen; Tu, Hui-Zin; Liu, Yung-Ching
      Journal of Antimicrobial Chemotherapy (2005), 56 (6), 1058-1062CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      Fluoroquinolones are being used more frequently for the treatment of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis complex (MTB). This study was designed to det. the frequency of the emergence of fluoroquinolone-resistant strains in Taiwan and to assess whether this might be due to use of fluoroquinolones for treatment of patients with MDR or because of increased use of fluoroquinolones in the community for treatment of other infections. The authors also sought to det. whether there might be clonal spread of fluoroquinolone resistance. A total of 3497 clin. isolates of M. tuberculosis complex were obtained during 1995-2003, of which 141 were selected. They consisted of 62 isolates fully susceptible to four first-line drugs, 33 isolates resistant to rifampicin and isoniazid (MDR), and 46 isolates with a variety of any drug resistant patterns other than MDR (combination group). The MICs were detd. for ciprofloxacin, ofloxacin and levofloxacin. Results: An increase in the MIC90 and rates of resistance to ciprofloxacin, ofloxacin and levofloxacin were noted only in the MDR group. The rates were higher among strains isolated between 1998-2003 compared with those obtained between 1995-1997 (rate of resistance, 20% vs. 7.7%; MIC ≥ 4 mg/L vs. 1-2 mg/L). Among the 10 fluoroquinolone-resistant isolates, 5 (50%) possessed mutations other than S95T in the gyrA gene. No gyrB mutation was found in any of the clin. isolates. These findings suggest that fluoroquinolone resistance is the result of treatment of patients with MDR strains rather than from use in the general community in Taiwan. The emergence of fluoroquinolone resistance among MDR strains reinforces the need for routine fluoroquinolone susceptibility testing whenever these drugs might be used.
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    12. 12
      Lee, A. S.; Tang, L. L.; Lim, I. H.; Wong, S. Y. Characterization of pyrazinamide and ofloxacin resistance among drug resistant Mycobacterium tuberculosis isolates from Singapore. Int. J. Infect. Dis. 2002, 6, 48– 51,  DOI: 10.1016/s1201-9712(02)90136-0
      12
      Characterization of pyrazinamide and ofloxacin resistance among drug resistant Mycobacterium tuberculosis isolates from Singapore
      Lee Ann S G; Tang Lynn L H; Lim Irene H K; Wong Sin Yew
      International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (2002), 6 (1), 48-51 ISSN:1201-9712.
      OBJECTIVES: To evaluate rapid molecular approaches for the detection of pyrazinamide (PZA) and ofloxacin resistance, by screening 100 known drug-resistant Mycobacterium tuberculosis isolates. METHODS: Mycobacterium tuberculosis isolates were tested for phenotypic resistance to pyrazinamide and ofloxacin using the BACTEC 460 radiometric method and the E-test, respectively. Mutation screening was done by amplifying the pncA, gyrA, and gyrB genes by the polymerase chain reaction (PCR) and direct automated sequencing. RESULTS: Twelve isolates were PZA-resistant and 8 of 12 (66.7%) isolates had missense mutations or deletions at the pncA gene, suggesting that mutation or deletion at the pncA gene is the major molecular mechanism of PZA resistance among the Singaporean isolates. Using the E-test, 48 isolates were resistant to ofloxacin, with minimum inhibitory concentrations of 4 microg/mL or higher. No mutations were observed at the quinolone resistance-determining region (QRDR) of gyrA in all isolates. At the QRDR of gyrB, mutations were present in 1 of 48 ofloxacin-resistant isolates and 0 of 19 ofloxacin-susceptible isolates. CONCLUSIONS: In Singapore, genotypic analysis of resistance to PZA and ofloxacin is inadequate and should be complemented by conventional methods.
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    13. 13
      Maruri, F.; Sterling, T. R.; Kaiga, A. W.; Blackman, A.; van der Heijden, Y. F.; Mayer, C.; Cambau, E.; Aubry, A. A systematic review of gyrase mutations associated with fluoroquinolone–resistant Mycobacterium tuberculosis and a proposed gyrase numbering system. J. Antimicrob. Chemother. 2012, 67, 819– 831,  DOI: 10.1093/jac/dkr566
      13
      A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system
      Maruri, Fernanda; Sterling, Timothy R.; Kaiga, Anne W.; Blackman, Amondrea; van der Heijden, Yuri F.; Mayer, Claudine; Cambau, Emmanuelle; Aubry, Alexandra
      Journal of Antimicrobial Chemotherapy (2012), 67 (4), 819-831CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      Fluoroquinolone resistance in Mycobacterium tuberculosis has become increasingly important. A review of mutations in DNA gyrase, the fluoroquinolone target, is needed to improve the mol. detection of resistance. The authors performed a systematic review of studies reporting mutations in DNA gyrase genes in clin. M. tuberculosis isolates. From 42 studies that met inclusion criteria, 1220 fluoroquinolone-resistant M. tuberculosis isolates underwent sequencing of the quinolone resistance-detg. region (QRDR) of gyrA; 780 (64%) had mutations. The QRDR of gyrB was sequenced in 534 resistant isolates; 17 (3%) had mutations. Mutations at gyrA codons 90, 91 or 94 were present in 654/1220 (54%) resistant isolates. Four different GyrB numbering systems were reported, resulting in mutation location discrepancies. The authors propose a consensus numbering system. Most fluoroquinolone-resistant M. tuberculosis isolates had mutations in DNA gyrase, but a substantial proportion did not. The proposed consensus numbering system can improve mol. detection of resistance and identification of novel mutations.
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    14. 14
      Pitaksajjakul, P.; Wongwit, W.; Punprasit, W.; Eampokalap, B.; Peacock, S.; Ramasoota, P. Mutations in the GyrA and GyrB genes of fluoroquinolone–resistant Mycobacterium tuberculosis from TB patients in Thailand. Southeast Asian J. Trop. Med. Public Health 2005, 36, 228– 237
      14
      Mutations in the gyrA and gyrB genes of fluoroquinolone-resistant Mycobacterium tuberculosis from TB patients in Thailand
      Pitaksajjakul, Pannamthip; Wongwit, Waranya; Punprasit, Wantanee; Eampokalap, Boonchuy; Peacock, Sharon; Ramasoota, Pongrama
      Southeast Asian Journal of Tropical Medicine and Public Health (2005), 36 (Suppl. 4), 228-237CODEN: SJTMAK; ISSN:0125-1562. (SEAMEO-TROPMED Network)
      Among fluoroquinolone-resistant Mycobacterium tuberculosis (FQr-MTB) isolates, mutation at positions 90, 91, and 94 in gyrA gene and at positions 495, 516, and 533 in gyrB gene have been frequently reported. In this study, 35 isolates of FQr-MTB were collected from Siriraj Hospital and Chest Disease Institute. The quinolone-resistance-detg. regions (QRDR) of gyrA and gyrB genes in all 35 FQr-MTB isolates and from the H37Ra MTB strain were amplified using polymerase chain reaction (PCR). DNA-sequencing and single-strand conformation polymorphism (SSCP) were further utilized for characterization of the mutations in the QRDR of gyrA and gyrB genes and mutation screening, resp. From DNA-sequencing, 21 of 35 (60%) exhibited single-point mutations in different positions, at Ala90Val, Ser91Pro, and Asp94(Gly/Ala/His/Asn); and one novel mutation position at Gly88Cys in the gyrA gene and Asp495Asn in the gyrB gene. These positions were previously frequently reported to be responsible for FQr-MTB. The other 14 FQr-MTB isolates (40%) had no mutation. This study is the first report of mutation occurring only in the QRDR of the gyrB gene, without prior mutation in the gyrA QRDR among FQr-MTB isolates. By SSCP anal. for screening of the mutant FQr-MTB, the SSCP patterns of mutated FQr-MTB isolates were clearly differentiated from the SSCP patterns of FQs-MTB.
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    15. 15
      Pitaksajjakul, P.; Worakhunpiset, S.; Chaiprasert, A.; Boonyasopun, J.; Ramasoota, P. GyrA and GyrB mutations in ofloxacin–resistant Mycobacterium tuberculosis clinical isolates in Thailand. Southeast Asian J. Trop. Med. Public Health. 2011, 42, 1163– 1167
      15
      gyrA and gyrB mutations in ofloxacin-resistant Mycobacterium tuberculosis clinical isolates in Thailand
      Pitaksajjakul, Pannamthip; Worakhunpiset, Suwalee; Chaiprasert, Angkana; Boonyasopun, Jirakarn; Ramasoota, Pongrama
      Southeast Asian Journal of Tropical Medicine and Public Health (2011), 42 (5), 1163-1167CODEN: SJTMAK; ISSN:0125-1562. (SEAMEO-TROPMED Network)
      In order to identify mutations in gyrA and gyrB genes in 92 ofloxacin-resistant Mycobacterium tuberculosis (OFXr-MTB) clin. isolates collected from Siriraj Hospital, Mahidol University and Chest Disease Institute, Thailand. The quinolone resistance-detg. regions (QRDR) of gyrA and gyrB in all 92 OFXr-MTB isolates were amplified using polymerase chain reaction and sequenced. There were 70 isolates with point mutations assocd. with ofloxacin resistance. In gyrA QRDR, 69 isolates had mutations in gyrA Gly88 (Ala/(75), Ala90 (Val), Ser91 (Pro) and Asp94 (Gly/Ala/His/Asn), the latter being the most common (42%). Only one isolate was found with mutation at position Asp495 (Asn). The other 22 isolates had no mutations in both gyrA and gyrB QRDR. Thus, point mutations in gyrA and gyrB QRDR were responsible for OFXr-MTB clin. isolates in Thailand.
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    16. 16
      Soudani, A.; Hadjfredj, S.; Zribi, M.; Messaoud, T.; Masmoudi, A.; Majed, B.; Fendri, C. First report of molecular characterization of fluoroquinolone–resistant Mycobacterium tuberculosis isolates from a Tunisian hospital. Clin. Microbiol. Infect. 2010, 16, 1454– 1457,  DOI: 10.1111/j.1469-0691.2010.03087.x
      There is no corresponding record for this reference.
    17. 17
      Medapi, B.; Renuka, J.; Saxena, S.; Sridevi, J. P.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Design and synthesis of novel quinoline–aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyrase B inhibitors. Bioorg. Med. Chem. 2015, 23, 2062– 2078,  DOI: 10.1016/j.bmc.2015.03.004
      There is no corresponding record for this reference.
    18. 18
      Medapi, B.; Suryadevara, P.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. 4–Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation. Eur. J. Med. Chem. 2015, 103, 1– 16,  DOI: 10.1016/j.ejmech.2015.06.032
      There is no corresponding record for this reference.
    19. 19
      Jeankumar, V. U.; Reshma, R. S.; Vats, R.; Janupally, R.; Saxena, S.; Yogeeswari, P.; Sriram, D. Engineering another class of anti–tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors. Eur. J. Med. Chem. 2016, 122, 216– 231,  DOI: 10.1016/j.ejmech.2016.06.042
      There is no corresponding record for this reference.
    20. 20
      Jeankumar, V. U.; Renuka, J.; Pulla, V. K.; Soni, V.; Sridevi, J. P.; Suryadevara, P.; Shravan, M.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Development of novel N–linked aminopiperidine–based mycobacterial DNA gyrase B inhibitors: scaffold hopping from known antibacterial leads. Int. J. Antimicrob Agents. 2014, 43, 269– 278,  DOI: 10.1016/j.ijantimicag.2013.12.006
      There is no corresponding record for this reference.
    21. 21
      Jeankumar, V. U.; Kotagiri, S.; Janupally, R.; Suryadevara, P.; Sridevi, J. P.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Exploring the gyrase ATPase domain for tailoring newer anti–tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors. Bioorg. Med. Chem. 2015, 23, 588– 601,  DOI: 10.1016/j.bmc.2014.12.001
      There is no corresponding record for this reference.
    22. 22
      Omar, M. A.; Masaret, G. S.; Abbas, E. M. H.; Abdel Aziz, M. M.; Harras, M. F.; Farghaly, T. A. Novel anti–tubercular and antibacterial based benzosuberone–thiazole moieties: synthesis, molecular docking analysis, DNA gyrase supercoiling and ATPase activity. Bioorg Chem. 2020, 104, 104316  DOI: 10.1016/j.bioorg.2020.104316
      There is no corresponding record for this reference.
    23. 23
      Jeankumar, V. U.; Renuka, J.; Kotagiri, S.; Saxena, S.; Kakan, S. S.; Sridevi, J. P.; Yellanki, S.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Gyrase ATPase domain as an antitubercular drug discovery platform: structure–based design and lead optimization of nitrothiazolyl carboxamide analogues. Chem. Med. Chem. 2014, 9, 1850– 1859,  DOI: 10.1002/cmdc.201402035
      There is no corresponding record for this reference.
    24. 24
      P, S. H.; Solapure, S.; Mukherjee, K.; Nandi, V.; Waterson, D.; Shandil, R.; Balganesh, M.; Sambandamurthy, V. K.; Raichurkar, A. K.; Deshpande, A.; Ghosh, A.; Awasthy, D.; Shanbhag, G.; Sheikh, G.; McMiken, H.; Puttur, J.; Reddy, J.; Werngren, J.; Read, J.; Kumar, M.; M, R.; Chinnapattu, M.; Madhavapeddi, P.; Manjrekar, P.; Basu, R.; Gaonkar, S.; Sharma, S.; Hoffner, S.; Humnabadkar, V.; Subbulakshmi, V.; Panduga, V. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure–activity relationship and in vivo efficacy in a mouse model of tuberculosis. Antimicrob. Agents Chemother. 2014, 58, 61– 70,  DOI: 10.1128/AAC.01751-13
      There is no corresponding record for this reference.
    25. 25
      Reddy, K. I.; Srihari, K.; Renuka, J.; Sree, K. S.; Chuppala, A.; Jeankumar, V. U.; Sridevi, J. P.; Babu, K. S.; Yogeeswari, P.; Sriram, D. An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition. Bioorg. Med. Chem. 2014, 22, 6552– 6563,  DOI: 10.1016/j.bmc.2014.10.016
      25
      An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition
      Reddy, Kummetha Indrasena; Srihari, Konduri; Renuka, Janupally; Sree, Komanduri Shruthi; Chuppala, Aruna; Jeankumar, Variam Ullas; Sridevi, Jonnalagadda Padma; Babu, Kondra Sudhakar; Yogeeswari, Perumal; Sriram, Dharmarajan
      Bioorganic & Medicinal Chemistry (2014), 22 (23), 6552-6563CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      A series of twenty eight mols. of Et 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by mol. hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorometry. Also the orientation and the ligand-protein interactions of the top hit mols. with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compds. studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a pos. shift of 3.5 °C in differential scanning fluorimetric evaluations.
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    26. 26
      Renuka, J.; Reddy, K. I.; Srihari, K.; Jeankumar, V. U.; Shravan, M.; Sridevi, J. P.; Yogeeswari, P.; Babu, K. S.; Sriram, D. Design, synthesis, biological evaluation of substituted benzofurans as DNA gyrase B inhibitors of Mycobacterium tuberculosis. Bioorg. Med. Chem. 2014, 22, 4924– 4934,  DOI: 10.1016/j.bmc.2014.06.041
      26
      Design, synthesis, biological evaluation of substituted benzofurans as DNA gyrase B inhibitors of Mycobacterium tuberculosis
      Renuka, Janupally; Reddy, Kummetha Indrasena; Srihari, Konduri; Jeankumar, Variam Ullas; Shravan, Morla; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Babu, Kondra Sudhakar; Sriram, Dharmarajan
      Bioorganic & Medicinal Chemistry (2014), 22 (17), 4924-4934CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well established and validated target for the development of novel therapeutics. The authors present the discovery and optimization of an Et 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyrase B inhibitors, selected from the Birla Institute of Technol. and Science (BITS) database chem. library of about 3000 mols. When these compds. were tested for their biol. activity, the compd. 22 emerged as the most active potent lead with an IC50 of 3.2 ± 0.15 μM against Mycobacterium smegmatis DNA gyrase B enzyme and 0.81 ± 0.24 μM in MTB supercoiling activity. The binding of this most active compd. to the DNA gyrase B enzyme and its thermal stability was further characterized using a differential scanning fluorimetry method.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlGmu7bM&md5=4e84e0c1d803e5579a10314a199872d4
    27. 27
      Jeankumar, V. U.; Saxena, S.; Vats, R.; Reshma, R. S.; Janupally, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Structure–guided discovery of antitubercular agents that target the gyrase ATPase domain. Chem. Med. Chem. 2016, 11, 539– 548,  DOI: 10.1002/cmdc.201500556
      There is no corresponding record for this reference.
    28. 28
      Saxena, S.; Samala, G.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. Development of 2–amino–5–phenylthiophene–3–carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain. Bioorg. Med. Chem. 2015, 23, 1402– 1412,  DOI: 10.1016/j.bmc.2015.02.032
      There is no corresponding record for this reference.
    29. 29
      Saxena, S.; Renuka, J.; Yogeeswari, P.; Sriram, D. Discovery of novel mycobacterial DNA gyrase B inhibitors: In silico and in vitro biological evaluation. Mol. Inform. 2014, 33, 597– 609,  DOI: 10.1002/minf.201400058
      There is no corresponding record for this reference.
    30. 30
      McGarry, D. H.; Cooper, I. R.; Walker, R.; Warrilow, C. E.; Pichowicz, M.; Ratcliffe, A. J.; Salisbury, A. M.; Savage, V. J.; Moyo, E.; Maclean, J.; Smith, A.; Charrier, C.; Stokes, N. R.; Lindsay, D. M.; Kerr, W. J. Design, synthesis and antibacterial properties of pyrimido[4,5–b]indol–8–amine inhibitors of DNA gyrase. Bioorg. Med. Chem. Lett. 2018, 28, 2998– 3003,  DOI: 10.1016/j.bmcl.2018.05.049
      There is no corresponding record for this reference.
    31. 31
      Henderson, S. R.; Stevenson, C. E. M.; Malone, B.; Zholnerovych, Y.; Mitchenall, L. A.; Pichowicz, M.; McGarry, D. H.; Cooper, I. R.; Charrier, C.; Salisbury, A. M.; Lawson, D. M.; Maxwell, A. Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase. J. Antimicrob. Chemother. 2020, 75, 2835– 2842,  DOI: 10.1093/jac/dkaa286
      31
      Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase
      Henderson, Sara R.; Stevenson, Clare E. M.; Malone, Brandon; Zholnerovych, Yelyzaveta; Mitchenall, Lesley A.; Pichowicz, Mark; McGarry, David H.; Cooper, Ian R.; Charrier, Cedric; Salisbury, Anne-Marie; Lawson, David M.; Maxwell, Anthony
      Journal of Antimicrobial Chemotherapy (2020), 75 (10), 2835-2842CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
      To evaluate the efficacy of two novel compds. against mycobacteria and det. the mol. basis of their action on DNA gyrase using structural and mechanistic approaches. Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallog. was used to det. the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. Both compds., Redx03863 and Redx04739, were active against selected Gram-pos. and Gram-neg. species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compds. were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compds. could have potential to be further exploited as antibiotics.
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    32. 32
      Kamsri, B.; Pakamwong, B.; Thongdee, P.; Phusi, N.; Kamsri, P.; Punkvang, A.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Sangswan, J.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Leanpolchareanchai, J.; Goudar, K. E.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity. J. Chem. Inf Model. 2023, 63, 2707– 2718,  DOI: 10.1021/acs.jcim.2c01376
      There is no corresponding record for this reference.
    33. 33
      Pakamwong, B.; Thongdee, P.; Kamsri, B.; Phusi, N.; Kamsri, P.; Punkvang, A.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Ariyachaokun, K.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis. J. Chem. Inf Model. 2022, 62, 1680– 1690,  DOI: 10.1021/acs.jcim.1c01390
      33
      Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis
      Pakamwong, Bongkochawan; Thongdee, Paptawan; Kamsri, Bundit; Phusi, Naruedon; Kamsri, Pharit; Punkvang, Auradee; Ketrat, Sombat; Saparpakorn, Patchreenart; Hannongbua, Supa; Ariyachaokun, Kanchiyaphat; Suttisintong, Khomson; Sureram, Sanya; Kittakoop, Prasat; Hongmanee, Poonpilas; Santanirand, Pitak; Spencer, James; Mulholland, Adrian J.; Pungpo, Pornpan
      Journal of Chemical Information and Modeling (2022), 62 (7), 1680-1690CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Mycobacterium tuberculosis DNA gyrase manipulates the DNA topol. using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biol. assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compd. library (www.specs.net). Thirty compds. were identified and selected as hits for in vitro biol. assays, of which two compds., G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concn. of 12.5 μg/mL. The two compds. inhibited DNA gyrase ATPase activity with IC50 values of 2.69 and 2.46 μM, resp., suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compds. I and II bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by mol. dynamics simulations followed by pharmacophore mapping anal., showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compd. lipophilicity by increasing the polarity of these tails then presents a likely route to improving the soly. and activity. Thus, compds. I and II provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.
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    34. 34
      Maxwell, A. The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 1993, 9, 681– 686,  DOI: 10.1111/j.1365-2958.1993.tb01728.x
      34
      The interaction between coumarin drugs and DNA gyrase
      Maxwell, Anthony
      Molecular Microbiology (1993), 9 (4), 681-6CODEN: MOMIEE; ISSN:0950-382X.
      A review with 49 refs. The coumarin group of antibiotics have as their target bacterial DNA gyrase (I). The drugs bind to the B subunit of I and inhibit DNA supercoiling by blocking the ATPase activity. Recent data show that the binding site for the drugs lies within the N-terminal part of the B protein, and individual amino acids involved in coumarin interaction are being identified. The mode of inhibition of the I ATPase reaction by coumarins is unlikely to be simple competitive inhibition, and the drugs may act by stabilizing a conformation of the enzyme with low affinity for ATP.
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    35. 35
      Grossman, S.; Fishwick, C. W. G.; McPhillie, M. J. Developments in non–intercalating bacterial topoisomerase inhibitors: allosteric and ATPase inhibitors of DNA gyrase and topoisomerase IV. Pharm. 2023, 16, 261,  DOI: 10.3390/ph16020261
      There is no corresponding record for this reference.
    36. 36
      Kar, S.; Roy, K. How far can virtual screening take us in drug discovery?. Expert Opin Drug Discovery 2013, 8, 245– 261,  DOI: 10.1517/17460441.2013.761204
      There is no corresponding record for this reference.
    37. 37
      Lionta, E.; Spyrou, G.; Vassilatis, D. K.; Cournia, Z. Structure–based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top Med. Chem. 2014, 14, 1923– 1938,  DOI: 10.2174/1568026614666140929124445
      37
      Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances
      Lionta, Evanthia; Spyrou, George; Vassilatis, Demetrios K.; Cournia, Zoe
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (16), 1923-1938CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the mol. basis of a disease and utilizes the knowledge of the three-dimensional structure of the biol. target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of top scoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.
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    38. 38
      Oliveira, T. A. D.; Silva, M. P. D.; Maia, E. H. B.; Silva, A. M. D.; Taranto, A. G. Virtual screening algorithms in drug discovery: a review focused on machine and deep learning methods. Drugs Drug Candidates. 2023, 2, 311– 334,  DOI: 10.3390/ddc2020017
      There is no corresponding record for this reference.
    39. 39
      Thongdee, P.; Hanwarinroj, C.; Pakamwong, B.; Kamsri, P.; Punkvang, A.; Leanpolchareanchai, J.; Ketrat, S.; Saparpakorn, P.; Hannongbua, S.; Ariyachaokun, K.; Suttisintong, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Mukamolova, G. V.; Blood, R. A.; Takebayashi, Y.; Spencer, J.; Mulholland, A. J.; Pungpo, P. Virtual screening identifies novel and potent inhibitors of Mycobacterium tuberculosis PknB with antibacterial activity. J. Chem. Inf Model. 2022, 62, 6508– 6518,  DOI: 10.1021/acs.jcim.2c00531
      There is no corresponding record for this reference.
    40. 40
      Arica Sosa, A.; Alcántara, R.; Jiménez Avalos, G.; Zimic, M.; Milón, P.; Quiliano, M. Identifying RO9021 as a potential inhibitor of PknG from Mycobacterium tuberculosis: combinative computational and in vitro studies. ACS Omega. 2022, 7, 20204– 20218,  DOI: 10.1021/acsomega.2c02093
      There is no corresponding record for this reference.
    41. 41
      41. Sheikh, B. A.; Bhat, B. A.; Rizvi, M. A.; Ahmad, Z.; Almilaibary, A.; Alkhanani, M.; Mir, M. A. Computational studies to identify potential inhibitors targeting the DprE1 protein in Mycobacterium tuberculosis. Int. J. Pharm. Investig. 2023, 13, 129– 138,  DOI: 10.5530/223097131750
      There is no corresponding record for this reference.
    42. 42
      Verma, A.; Kumar, V.; Naik, B.; Khan, J. M.; Singh, P.; Saris, P. E. J.; Gupta, S. Screening and molecular dynamics simulation of compounds inhibiting MurB enzyme of drug–resistant Mycobacterium tuberculosis: An in–silico approach. Saudi J. Biol. Sci. 2023, 30, 103730  DOI: 10.1016/j.sjbs.2023.103730
      There is no corresponding record for this reference.
    43. 43
      Kumar, G. S.; Dubey, A.; Panda, S. P.; Alawi, M. M.; Sindi, A. A.; Azhar, E. I.; Dwivedi, V. D.; Agrawal, S. Repurposing of antibacterial compounds for suppression of Mycobacterium tuberculosis dormancy reactivation by targeting resuscitation–promoting factors B. J. Biomol. Struct. Dyn. 2023, 1– 13,  DOI: 10.1080/07391102.2023.2245059
      There is no corresponding record for this reference.
    44. 44
      Johannsen, S.; Gierse, R. M.; Olshanova, A.; Smerznak, E.; Laggner, C.; Eschweiler, L.; Adeli, Z.; Hamid, R.; Alhayek, A.; Reiling, N.; Haupenthal, J.; Hirsch, A. K. H. Not every hit–identification technique works on 1–deoxy–d–xylulose 5–phosphate synthase (DXPS): making the most of a virtual screening campaign. ChemMedChem 2023, 18, e202200590  DOI: 10.1002/cmdc.202200590
      There is no corresponding record for this reference.
    45. 45
      Damera, T.; Kondaparthi, V.; Bingi, M.; Mustyala, K. K.; Malkhed, V. Identification of novel scaffolds to inhibit Mycobacterium tuberculosis PimA protein–A computational approach. J. Cell Biochem. 2023, 124, 836– 848,  DOI: 10.1002/jcb.30412
      There is no corresponding record for this reference.
    46. 46
      Varon, H. A.; Santos, P.; Lopez-Vallejo, F.; Soto, C. Y. Novel scaffolds targeting Mycobacterium tuberculosis plasma membrane Ca2+ transporter CtpF by structure–based strategy. Bioorg. Chem. 2023, 138, 106648  DOI: 10.1016/j.bioorg.2023.106648
      There is no corresponding record for this reference.
    47. 47
      Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug–likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717,  DOI: 10.1038/srep42717
      47
      SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules
      Daina Antoine; Michielin Olivier; Zoete Vincent; Michielin Olivier; Michielin Olivier
      Scientific reports (2017), 7 (), 42717 ISSN:.
      To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
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    48. 48
      Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B. A.; Thiessen, P. A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E. E. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021, 49, D1388– D1395,  DOI: 10.1093/nar/gkaa971
      48
      PubChem in 2021: new data content and improved web interfaces
      Kim, Sunghwan; Chen, Jie; Cheng, Tiejun; Gindulyte, Asta; He, Jia; He, Siqian; Li, Qingliang; Shoemaker, Benjamin A.; Thiessen, Paul A.; Yu, Bo; Zaslavsky, Leonid; Zhang, Jian; Bolton, Evan E.
      Nucleic Acids Research (2021), 49 (D1), D1388-D1395CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      PubChem is a popular chem. information resource that serves the scientific community as well as the general public, with millions of unique users per mo. In the past 2 yr, PubChem made substantial improvements. Data from >100 new data sources were added to PubChem, including chem.-literature links from Thieme Chem., chem. and phys. property links from SpringerMaterials, and patent links from the World Intellectual Properties Organization (WIPO). PubChem's homepage and individual record pages were updated to help users find desired information faster. This update involved a data model change for the data objects used by these pages as well as by programmatic users. Several new services were introduced, including the PubChem Periodic Table and Element pages, Pathway pages, and Knowledge panels. Addnl., in response to the coronavirus disease 2019 (COVID-19) outbreak, PubChem created a special data collection that contains PubChem data related to COVID-19 and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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    49. 49
      Backman, T. W. H.; Cao, Y.; Girke, T. ChemMine tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res. 2011, 39, W486– W491,  DOI: 10.1093/nar/gkr320
      49
      ChemMine tools: an online service for analyzing and clustering small molecules
      Backman, Tyler W. H.; Cao, Yiqun; Girke, Thomas
      Nucleic Acids Research (2011), 39 (Web Server), W486-W491CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      ChemMine Tools is an online service for small mol. data anal. It provides a web interface to a set of chemoinformatics and data mining tools that are useful for various anal. routines performed in chem. genomics and drug discovery. The service also offers programmable access options via the R library ChemmineR. The primary functionalities of ChemMine Tools fall into five major application areas: data visualization, structure comparisons, similarity searching, compd. clustering and prediction of chem. properties. First, users can upload compd. data sets to the online Compd. Workbench. Numerous utilities are provided for compd. viewing, structure drawing and format interconversion. Second, pairwise structural similarities among compds. can be quantified. Third, interfaces to ultra-fast structure similarity search algorithms are available to efficiently mine the chem. space in the public domain. These include fingerprint and embedding/indexing algorithms. Fourth, the service includes a Clustering Toolbox that integrates chemoinformatic algorithms with data mining utilities to enable systematic structure and activity based analyses of custom compd. sets. Fifth, physicochem. property descriptors of custom compd. sets can be calcd. These descriptors are important for assessing the bioactivity profile of compds. in silico and quant. structure-activity relationship (QSAR) analyses. ChemMine Tools is available at: http://chemmine.ucr.edu.
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    50. 50
      Studier, F. W.; Moffatt, B. A. Use of bacteriophage T7 RNA polymerase to direct selective high–level expression of cloned genes. J. Mol. Biol. 1986, 189, 113– 130,  DOI: 10.1016/0022-2836(86)90385-2
      50
      Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes
      Studier, F. William; Moffatt, Barbara A.
      Journal of Molecular Biology (1986), 189 (1), 113-30CODEN: JMOBAK; ISSN:0022-2836.
      A gene expression system based on phage T7 RNA polymerase [9014-24-8] was developed. T7 RNA polymerase is highly selective for its own promoters, which do not occur naturally in Escherichia coli. A relatively small amt. of T7 RNA polymerase provided from a cloned copy of T7 gene 1 is sufficient to direct high-level transcription from a T7 promoter in a multicopy plasmid. Such transcription can proceed several times around the plasmid without terminating and can be so active that transcription by E. coli RNA polymerase is greatly decreased. When a cleavage site for RNase III is introduced, discrete RNAs of plasmid length can accumulate. The natural transcription terminator from T7 DNA also works effectively in the plasmid. Both the rate of synthesis and the accumulation of RNA directed by T7 RNA polymerase can reach levels comparable with those for rRNAs in a normal cell. These high levels of accumulation suggest that the RNAs are relatively stable, perhaps in part because their great length and(or) stem-and-loop structures at their 3' ends help to protect them against exonucleolytic degrdn. Apparently, a specific mRNA produced by T7 RNA polymerase can rapidly sat. the translational machinery of E. coli, so that the rate of protein synthesis from such an mRNA will depend primarily on the efficiency of its translation. When the mRNA is efficiently translated, a target protein can accumulate to >50% of the total cell protein in ≤3 h. Two ways were used to deliver active T7 RNA polymerase to the cell: (1) infection by a λ deriv. that carried gene 1; or (2) induction of a chromosomal copy of gene 1 under control of the lacUV5 promoter. When gene 1 is delivered by infection, very toxic target genes can be maintained silently in the cell until T7 RNA polymerase is introduced, when they rapidly become expressed at high levels. When gene 1 is resident in the chromosome, even the very low basal levels of T7 RNA polymerase present in the uninduced cell can prevent the establishment of plasmids carrying toxic target genes, or make the plasmid unstable. But if the target plasmid can be maintained, induction of chromosomal gene 1 can be a convenient way to produce large amts. of target RNA and(or) protein. T7 RNA polymerase seems to be capable of transcribing almost any DNA linked to a T7 promoter, so the T7 expression system should be capable of transcribing almost any gene or its complement in E. coli. Comparable T7 expression systems can be developed in other types of cells.
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    51. 51
      Laemmli, U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970, 227, 680– 685,  DOI: 10.1038/227680a0
      51
      Cleavage of structural proteins during the assembly of the head of bacteriophage T4
      Laemmli, U. K.
      Nature (London, United Kingdom) (1970), 227 (5259), 680-685CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Using an improved method of polyacrylamide gel electrophoresis based on the capability of SDS to break down proteins into their individual polypeptide chains, many previously unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products. Four major components of the head are cleaved during the process of assembly, apparently after the precursor proteins have assembled into some large intermediate structure.
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    52. 52
      Wang, X. D.; Meng, M. X.; Gao, L. B.; Liu, T.; Xu, Q.; Zeng, S. Permeation of astilbin and taxifolin in Caco–2 cell and their effects on the P–gp. Int. J. Pharm. 2009, 378, 1– 8,  DOI: 10.1016/j.ijpharm.2009.05.022
      52
      Permeation of astilbin and taxifolin in Caco-2 cell and their effects on the P-gp
      Wang, Xiao-dan; Meng, Min-xin; Gao, Ling-bo; Liu, Ting; Xu, Qiang; Zeng, Su
      International Journal of Pharmaceutics (2009), 378 (1-2), 1-8CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      This study was designed to understand the transport profiles of astilbin and taxifolin in Caco-2 cell model and their effects on the function and expression of P-glycoprotein. The transport studies were examd. using Caco-2 cells cultured on Transwell inserts. Their effects on the function and expression of P-glycoprotein were detected using Western Blot and RT-PCR. The transport was concn. and temp. dependent. The apparent permeability (P app) of these two compds. in the secretory direction was larger than that in the absorptive direction in the concn. range of 10-1000 μM. Those compds. had no effects on the P-glycoprotein-mediated transport of Rhodamine 123. Caco-2 cells exposed to astilbin or taxifolin for 36 h exhibited higher P-glycoprotein activity through up-regulating P-glycoprotein expression at protein and mRNA levels. These results indicated that P-glycoprotein and Multidrug Resistance Protein 2 might play important roles in limiting the bioavailability of those compds. Drugs which are the inhibitors of P-glycoprotein or Multidrug Resistance Protein 2 may increase the oral bioavailability of astilbin or taxifolin and the possibility of unwanted drug-food interactions. The increased expression of P-glycoprotein in Caco-2 cells may serve as an adaptation and defense mechanism in limiting the entry of xenobiotics into the body.
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    53. 53
      Faralli, A.; Shekarforoush, E.; Ajalloueian, F.; Mendes, A. C.; Chronakis, I. S. In vitro permeability enhancement of curcumin across Caco–2 cells monolayers using electrospun xanthan–chitosan nanofibers. Carbohydr. Polym. 2019, 206, 38– 47,  DOI: 10.1016/j.carbpol.2018.10.073
      There is no corresponding record for this reference.
    54. 54
      Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessmen of docking accuracy. J. Med. Chem. 2004, 47, 1739– 1749,  DOI: 10.1021/jm0306430
      54
      Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
      Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
      Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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    55. 55
      Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra Precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J. Med. Chem. 2006, 49, 6177– 6196,  DOI: 10.1021/jm051256o
      55
      Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
      Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.; Frye, Leah L.; Greenwood, Jeremy R.; Halgren, Thomas A.; Sanschagrin, Paul C.; Mainz, Daniel T.
      Journal of Medicinal Chemistry (2006), 49 (21), 6177-6196CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A novel scoring function to est. protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addn. to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included:(1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce exptl. binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, resp.) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP mol. recognition and water scoring in sepg. active and inactive ligands and avoiding false positives.
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    56. 56
      Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 2004, 47, 1750– 1759,  DOI: 10.1021/jm030644s
      56
      Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
      Halgren, Thomas A.; Murphy, Robert B.; Friesner, Richard A.; Beard, Hege S.; Frye, Leah L.; Pollard, W. Thomas; Banks, Jay L.
      Journal of Medicinal Chemistry (2004), 47 (7), 1750-1759CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Glide's ability to identify active compds. in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compd. collection of a pharmaceutical or biotechnol. company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that av. measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of phys. chem., particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
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    57. 57
      Petrella, S.; Capton, E.; Raynal, B.; Giffard, C.; Thureau, A.; Bonneté, F.; Alzari, P. M.; Aubry, A.; Mayer, C. Overall Structures of Mycobacterium tuberculosis DNA Gyrase Reveal the Role of a Corynebacteriales GyrB-Specific Insert in ATPase Activity. Structure. 2019, 27, 579– 589,  DOI: 10.1016/j.str.2019.01.004
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      Overall Structures of Mycobacterium tuberculosis DNA Gyrase Reveal the Role of a Corynebacteriales GyrB-Specific Insert in ATPase Activity
      Petrella, Stephanie; Capton, Estelle; Raynal, Bertrand; Giffard, Clement; Thureau, Aurelien; Bonnete, Francoise; Alzari, Pedro M.; Aubry, Alexandra; Mayer, Claudine
      Structure (Oxford, United Kingdom) (2019), 27 (4), 579-589.e5CODEN: STRUE6; ISSN:0969-2126. (Elsevier Ltd.)
      Despite sharing common features, previous studies have shown that gyrases from different species have been modified throughout evolution to modulate their properties. Here, we report two crystal structures of Mycobacterium tuberculosis DNA gyrase, an apo and AMPPNP-bound form at 2.6-Å and 3.3-Å resoln., resp. These structures provide high-resoln. structural data on the quaternary organization and interdomain connections of a gyrase (full-length GyrB-GyrA57)2 thus providing crucial inputs on this essential drug target. Together with small-angle X-ray scattering studies, they revealed an "extremely open" N-gate state, which persists even in the DNA-free gyrase-AMPPNP complex and an unexpected connection between the ATPase and cleavage core domains mediated by two Corynebacteriales-specific motifs, resp. the C-loop and DEEE-loop. We show that the C-loop participates in the stabilization of this open conformation, explaining why this gyrase has a lower ATPase activity. Our results image a conformational state which might be targeted for drug discovery.
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    58. 58
      Agrawal, A.; Roue, M.; Spitzfaden, C.; Petrella, S.; Aubry, A.; Hann, M.; Bax, B.; Mayer, C. Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion. Biochem. J. 2013, 456, 263– 273,  DOI: 10.1042/BJ20130538
      58
      Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion
      Agrawal, Alka; Roue, Melanie; Spitzfaden, Claus; Petrella, Stephanie; Aubry, Alexandra; Hann, Michael; Bax, Benjamin; Mayer, Claudine
      Biochemical Journal (2013), 456 (2), 263-273CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
      DNA gyrase, a type II topoisomerase, regulates DNA topol. by creating a double-stranded break in one DNA duplex and transporting another DNA duplex [T-DNA (transported DNA)] through this break. The ATPase domains dimerize, in the presence of ATP, to trap the T-DNA segment. Hydrolysis of only one of the two ATPs, and release of the resulting Pi, is ratelimiting in DNA strand passage. A long unresolved puzzle is how the non-hydrolysable ATP analog AMP-PNP (adenosine 5'-[β,γ-imido]triphosphate) can catalyze one round of DNA strand passage without Pi release. In the present paper we discuss two crystal structures of the Mycobacterium tuberculosis DNA gyrase ATPase domain: one complexed with AMP-PCP (adenosine 5'-[β,γ-methylene]triphosphate) was unexpectedly monomeric, the other, an AMP-PNP complex, crystd. as a dimer. In the AMP-PNP structure, the unprotonated nitrogen (P-N=P imino) accepts hydrogen bonds from a well-ordered 'ATP lid', which is known to be required for dimerization. The equivalent CH2 group, in AMP-PCP, cannot accept hydrogen bonds, leaving the 'ATP lid' region disordered. Further anal. suggested that AMP-PNP can be converted from the imino (P-N=P) form into the imido form (P-NH-P) during the catalytic cycle. A main-chain NH is proposed to move to either protonate AMP-P-N=P to AMP-P-NH-P, or to protonate ATP to initiate ATP hydrolysis. This suggests a novel dissociative mechanism for ATP hydrolysis that could be applicable not only to GHKL phosphotransferases, but also to unrelated ATPases and GTPases such as Ras. On the basis of the domain orientation in our AMP-PCP structure we propose a mechanochem. scheme to explain how ATP hydrolysis is coupled to domain motion.
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    59. 59
      Shirude, P. S.; Madhavapeddi, P.; Tucker, J. A.; Murugan, K.; Patil, V.; Basavarajappa, H.; Raichurkar, A. V.; Humnabadkar, V.; Hussein, S.; Sharma, S.; Ramya, V. K.; Narayan, C. B.; Balganesh, T. S.; Sambandamurthy, V. K. Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis. ACS Chem. Biol. 2013, 8, 519– 523,  DOI: 10.1021/cb300510w
      59
      Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis
      Shirude, Pravin S.; Madhavapeddi, Prashanti; Tucker, Julie A.; Murugan, Kannan; Patil, Vikas; Basavarajappa, Halesha; Raichurkar, Anandkumar V.; Humnabadkar, Vaishali; Hussein, Syeed; Sharma, Sreevalli; Ramya, V. K.; Narayan, Chandan B.; Balganesh, Tanjore S.; Sambandamurthy, Vasan K.
      ACS Chemical Biology (2013), 8 (3), 519-523CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chem. tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.
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    60. 60
      Greenwood, J. R.; Calkins, D.; Sullivan, A. P.; Shelley, J. C. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug–like molecules in aqueous solution. J. Comput. Aided Mol. Des. 2010, 24, 591– 604,  DOI: 10.1007/s10822-010-9349-1
      60
      Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution
      Greenwood, Jeremy R.; Calkins, David; Sullivan, Arron P.; Shelley, John C.
      Journal of Computer-Aided Molecular Design (2010), 24 (6-7), 591-604CODEN: JCADEQ; ISSN:0920-654X. (Springer)
      A review. Generating the appropriate protonation states of drug-like mols. in soln. is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compds. requires a method for detg. tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximize enrichment, the lowest energy tautomers must be detd. from heterogeneous input, without over-enumerating unfavorable states. While computationally expensive, the d. functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett-Taft methodol. can very rapidly extrapolate substituent effects from model systems to drug-like mols. via the relationship between pKT and pKa. Combining the 2 complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited no. of measured pKT values, esp. for the complicated heterocycles often favored by medicinal chemists for their novelty and versatility. Several hundreds of pre-calcd. tautomer energies and substituent pKa effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aq. ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and exptl. data. Recommendations are made for how to best incorporate tautomers in mol. design and virtual screening workflows.
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    61. 61
      Shelley, J. C.; Cholleti, A.; Frye, L. L.; Greenwood, J. R.; Timlin, M. R.; Uchimaya, M. Epik: a software program for pKa prediction and protonation state generation for drug–like molecules. J. Comput. Aided Mol. Des. 2007, 21, 681– 691,  DOI: 10.1007/s10822-007-9133-z
      61
      Epik: a software program for pKa prediction and protonation state generation for drug-like molecules
      Shelley, John C.; Cholleti, Anuradha; Frye, Leah L.; Greenwood, Jeremy R.; Timlin, Mathew R.; Uchimaya, Makoto
      Journal of Computer-Aided Molecular Design (2007), 21 (12), 681-691CODEN: JCADEQ; ISSN:0920-654X. (Springer)
      Epik is a computer program for predicting pKa values for drug-like mols. Epik can use this capability in combination with technol. for tautomerization to adjust the protonation state of small drug-like mols. to automatically generate one or more of the most probable forms for use in further mol. modeling studies. Many medicinal chems. can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its soly. and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the mol., as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate mols. used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like mols. to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the mol. itself rather just for the particular Lewis structure used on input. In addn., a new iterative technol. for generating, ranking and culling the generated protonation states is employed.
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    62. 62
      Case, D. A.; Aktulga, H. M.; Belfon, K.; Ben Shalom, I. Y.; Brozell, S. R.; Cerutti, D. S.; Cheatham, III, T. E.; Cisneros, G. A.; Cruzeiro, V. W. D.; Darden, T. A.; Duke, R. E.; Giambasu, G.; Gilson, M. K.; Gohlke, H.; Goetz, A. W.; Harris, R.; Izadi, S.; Izmailov, S. A.; Jin, C.; Kasavajhala, K.; Kaymak, M. C.; King, E.; Kovalenko, A.; Kurtzman, T.; Lee, T. S.; LeGrand, S.; Li, P.; Lin, C.; Liu, J.; Luchko, T.; Luo, R.; Machado, M.; Man, V.; Manathunga, M.; Merz, K. M.; Miao, Y.; Mikhailovskii, O.; Monard, G.; Nguyen, H.; O’Hearn, K. A.; Onufriev, A.; Pan, F.; Pantano, S.; Qi, R.; Rahnamoun, A.; Roe, D. R.; Roitberg, A.; Sagui, C.; Schott Verdugo, S.; Shen, J.; Simmerling, C. L.; Skrynnikov, N. R.; Smith, J.; Swails, J.; Walker, R. C.; Wang, J.; Wei, H.; Wolf, R. M.; Wu, X.; Xue, Y.; York, D. M.; Zhao, S.; Kollman, P. A. Amber 2020; University of California: San Francisco, 2021.
      There is no corresponding record for this reference.
    63. 63
      Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 2004, 25, 1157– 1174,  DOI: 10.1002/jcc.20035
      63
      Development and testing of a general Amber force field
      Wang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.
      Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
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    64. 64
      Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A Well behaved electrostatic potential based method using charge restraints for deriving atomic charges: The RESP model. J. Phys. Chem. 1993, 97, 10269– 10280,  DOI: 10.1021/j100142a004
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      A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model
      Bayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy; Kollman, Peter A.
      Journal of Physical Chemistry (1993), 97 (40), 10269-80CODEN: JPCHAX; ISSN:0022-3654.
      The authors present a new approach to generating electrostatic potential (ESP) derived charges for mols. The major strength of electrostatic potential derived charges is that they optimally reproduce the intermol. interaction properties of mols. with a simple two-body additive potential, provided, of course, that a suitably accurate level of quantum mech. calcn. is used to derive the ESP around the mol. Previously, the major weaknesses of these charges have been that they were not easily transferably between common functional groups in related mols., they have often been conformationally dependent, and the large charges that frequently occur can be problematic for simulating intramol. interactions. Introducing restraints in the form of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the fit to the quantum mech. ESP. Several other refinements in addn. to the restrained electrostatic potential (RESP) fit yield a general and algorithmic charge fitting procedure for generating atom-centered point charges. This approach can thus be recommended for general use in mol. mechanics, mol. dynamics, and free energy calcns. for any org. or bioorg. system.
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    65. 65
      Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins. J. Comput. Chem. 1995, 16, 1357– 1377,  DOI: 10.1002/jcc.540161106
      65
      Application of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteins
      Cieplak, Piotr; Cornell, Wendy D.; Bayly, Christopher; Kollman, Peter A.
      Journal of Computational Chemistry (1995), 16 (11), 1357-77CODEN: JCCHDD; ISSN:0192-8651. (Wiley)
      The authors present the derivation of charges of ribo- and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calcns. with the 6-31G* basis set. For the nucleic acid fragments, the authors used electrostatic potentials of the four deoxyribonucleoside (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-mol. fitting and restrained electrostatic potential (RESP) fits, with Lagrangian multipliers ensuring a net charge of 0 or. The authors suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1' and H1' of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equiv. For peptide fragments, the authors have combined multiple conformation fitting, previously employed by Williams and Reynolds et al., with the RESP approach to derive charges for blocked dipeptides appropriate for each of the 20 naturally occurring amino acids. Based on the results for Pr amine, the authors suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of mols., provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms or hydrogens attached to heteroatoms. In these blocked dipeptide models, it is useful to require equiv. N-H and C=O charges for all amino acids with a given net charge (except proline), and this is accomplished in a straightforward fashion with multiple-mol. fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chem. blocked version of the residue. The multiple Lagrange constraints also enable charges from two or more mols. to be spliced together in a well-defined fashion. Thus, the combined use of multiple mols., multiple conformations, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers.
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    66. 66
      Fox, T.; Kollman, P. A. Application of the RESP methodology in the parametrization of organic solvents. J. Phys. Chem. B 1998, 102, 8070– 8079,  DOI: 10.1021/jp9717655
      66
      Application of the RESP Methodology in the Parametrization of Organic Solvents
      Fox, Thomas; Kollman, Peter A.
      Journal of Physical Chemistry B (1998), 102 (41), 8070-8079CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
      We present parameterizations for the nonaq. solvents DMSO, ethanol, CCl4, CHCl3, and CH2Cl2 that are compatible with the recent AMBER force field by Cornell et al. (J. Am. Chem. Soc. 1995, 117, 5179-5197). With the general procedure for generating new parameters and the RESP approach to obtain the at. charges, we achieve flexible all-atom solvent models whose d., heat of vaporization, diffusion const., and rotational correlation times are-esp. for a generic force field-in good agreement with available exptl. data.
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    67. 67
      Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983, 79, 926– 935,  DOI: 10.1063/1.445869
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      Comparison of simple potential functions for simulating liquid water
      Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
      Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
      Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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    68. 68
      Roe, D. R.; Cheatham, T., III. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J. Chem. Theory Comput. 2013, 9, 3084– 3095,  DOI: 10.1021/ct400341p
      68
      PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
      Roe, Daniel R.; Cheatham, Thomas E.
      Journal of Chemical Theory and Computation (2013), 9 (7), 3084-3095CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the anal. and processing of time series of three-dimensional at. positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange mol. dynamics), image with periodic boundary conditions, create av. structures, strip subsets of the system, and perform calcns. such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
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    69. 69
      Wang, E.; Sun, H.; Wang, J.; Wang, Z.; Liu, H.; Zhang, J. Z. H.; Hou, T. End–point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design. Chem. Rev. 2019, 119, 9478– 9508,  DOI: 10.1021/acs.chemrev.9b00055
      There is no corresponding record for this reference.
    70. 70
      Hou, T.; Yu, R. Molecular dynamics and free energy studies on the wild–type and double mutant HIV–1 protease complexed with amprenavir and two amprenavir–related inhibitors: mechanism for binding and drug resistance. J. Med. Chem. 2007, 50, 1177– 1188,  DOI: 10.1021/jm0609162
      70
      Molecular Dynamics and Free Energy Studies on the Wild-type and Double Mutant HIV-1 Protease Complexed with Amprenavir and Two Amprenavir-Related Inhibitors: Mechanism for Binding and Drug Resistance
      Hou, Tingjun; Yu, Ron
      Journal of Medicinal Chemistry (2007), 50 (6), 1177-1188CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The V82F/I84V double mutation is considered as the key residue mutation of the HIV-1 protease drug resistance because it can significantly lower the binding affinity of protease inhibitors in clin. uses. In the current work, the binding of amprenavir to both of the wild-type and the drug-resistant V82F/I84V mutant of the HIV-1 protease was investigated by mol. dynamics (MD) simulations and was compared to those of two inhibitors in development, TMC126 and TMC114. Abs. binding free energies were calcd. by mol. mechanics/Poisson-Boltzmann surface area (MM/ PBSA) methodol. The predicted binding affinities give a good explanation of structure-affinity relation (SAR) of three studied inhibitors. Furthermore, in the 18 ns MD simulations on the free wild-type and the mutated proteases, we obsd. that the free mutated protease shows similar dynamic characteristics of the flap opening and a little higher structural stability than the free wild-type protease. This suggests that the effect of the mutations may not significantly affect the equil. between the semi-open and the closed conformations. Finally, decompn. anal. of binding free energies and the further structural anal. indicate that the dominating effect of the V82F/I84V double mutation is to distort the geometry of the binding site and hence weaken the interactions of inhibitors pre-shaped to the wild-type binding site.
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    71. 71
      Li, W.; Zhang, J.; Guo, L.; Wang, Q. Importance of three–body problems and protein–protein interactions in proteolysis–targeting chimera modeling: Insights from molecular dynamics simulations. J. Chem. Inf. Model. 2022, 62, 523– 532,  DOI: 10.1021/acs.jcim.1c01150
      There is no corresponding record for this reference.
    72. 72
      Miller, B. R.; McGee, T. D.; Swails, J. M.; Homeyer, N.; Gohlke, H.; Roitberg, A. E. MMPBSA.py: An efficient program for end–state free energy calculations. J. Chem. Theory Comput. 2012, 8, 3314– 3321,  DOI: 10.1021/ct300418h
      72
      MMPBSA.py: An Efficient Program for End-State Free Energy Calculations
      Miller, Bill R., III; McGee, T. Dwight, Jr.; Swails, Jason M.; Homeyer, Nadine; Gohlke, Holger; Roitberg, Adrian E.
      Journal of Chemical Theory and Computation (2012), 8 (9), 3314-3321CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      MM-PBSA is a post-processing end-state method to calc. free energies of mols. in soln. MMPBSA.py is a program written in Python for streamlining end-state free energy calcns. using ensembles derived from mol. dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Ref. Interaction Site Model. Vibrational frequencies may be calcd. using normal mode or quasi-harmonic anal. to approx. the solute entropy. Specific interactions can also be dissected using free energy decompn. or alanine scanning. A parallel implementation significantly speeds up the calcn. by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calcns. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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    73. 73
      Onufriev, A.; Bashford, D.; Case, D. A. Exploring protein native states and large–scale conformational changes with a modified generalized born model. Proteins. 2004, 55, 383– 394,  DOI: 10.1002/prot.20033
      73
      Exploring protein native states and large-scale conformational changes with a modified Generalized Born model
      Onufriev, Alexey; Bashford, Donald; Case, David A.
      Proteins: Structure, Function, and Bioinformatics (2004), 55 (2), 383-394CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)
      Implicit solvation models provide, for many applications, a reasonably accurate and computationally effective way to describe the electrostatics of aq. solvation. Here, a popular anal. Generalized Born (GB) solvation model is modified to improve its accuracy in calcg. the solvent polarization part of free energy changes in large-scale conformational transitions, such as protein folding. In contrast to an earlier GB model (implemented in the AMBER-6 program), the improved version does not overstabilize the native structures relative to the finite-difference Poisson-Boltzmann continuum treatment. In addn. to improving the energy balance between folded and unfolded conformers, the algorithm (available in the AMBER-7 and NAB mol. modeling packages) is shown to perform well in more than 50 ns of native-state mol. dynamics (MD) simulations of thioredoxin, protein-A, and ubiquitin, as well as in a simulation of Barnase/Barstar complex formation. For thioredoxin, various combinations of input parameters have been explored, such as the underlying gas-phase force fields and the at. radii. The best performance is achieved with a previously proposed modification to the torsional potential in the Amber ff99 force field, which yields stable native trajectories for all of the tested proteins, with back-bone root-mean-square deviations from the native structures being ∼ 1.5 Å after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 Å relative to the crystal structure of the complex.
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    74. 74
      Weiser, J.; Shenkin, P. S.; Still, W. C. Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J. Comput. Chem. 1999, 20, 217– 230,  DOI: 10.1002/(SICI)1096-987X(19990130)20:2<217::AID-JCC4>3.0.CO;2-A
      74
      Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)
      Weiser, Jorg; Shenkin, Peter S.; Still, W. Clark
      Journal of Computational Chemistry (1999), 20 (2), 217-230CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      A fast anal. formula was derived for the calcn. of approx. at. and mol. van der Waals (vdWSA), and solvent-accessible surface areas (SASAs), as well as the first and second derivs. of these quantities with respect to at. coordinates. This method makes use of linear combinations of terms composed from pairwise overlaps of hard spheres; therefore, we term this the LCPO method for linear combination of pairwise overlaps. For higher performance, neighbor-list redn. (NLR) was applied as a preprocessing step. Eighteen compds. of different sizes (8-2366 atoms) and classes (org., proteins, DNA, and various complexes) were chosen as representative test cases. LCPO/NLR computed the SASA and first derivs. of penicillopepsin, a protein with 2366 atoms, in 0.87 s (0.22 s for the creation of the neighbor list, 0.35 s for NLR, and 0.30 s for SASA and first derivs.) on an SGI R10000/194 Mhz processor. This appears comparable to or better than timings reported previously for other algorithms. The vdWSAs were in good agreement with the numerical results: relative errors for total mol. surface areas ranged from 0.1 to 2.0% and av. abs. at. surface area deviations from 0.3 to 0.7 Å2. For SASAs without NLR, the LCPO method exhibited relative errors in the range of 0.4-9.2% for total mol. surface areas and av. abs. at. surface area deviations of 2.0-2.7 Å2; with NLR the relative mol. errors ranged from 0.1 to 7.8% and the av. abs. at. surface area deviation from 1.6 to 3.0 Å2.
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    75. 75
      Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2001, 46, 3– 26,  DOI: 10.1016/S0169-409X(00)00129-0
      75
      Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
      Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
      Advanced Drug Delivery Reviews (2001), 46 (1-3), 3-26CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
      A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is greater than 500 and the calcd. Log P (CLogP) is greater than 5 (or MlogP >4.15). Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
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    76. 76
      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
      76
      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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    77. 77
      Alt, S.; Mitchenall, L. A.; Maxwell, A.; Heide, L. Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. J. Antimicrob. Chemother. 2011, 66, 2061– 2069,  DOI: 10.1093/jac/dkr247
      77
      Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics
      Alt, Silke; Mitchenall, Lesley A.; Maxwell, Anthony; Heide, Lutz
      Journal of Antimicrobial Chemotherapy (2011), 66 (9), 2061-2069CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      Aminocoumarin antibiotics are potent inhibitors of bacterial DNA gyrase. We investigated the inhibitory and antibacterial activity of naturally occurring aminocoumarin antibiotics and six structural analogs (novclobiocins) against DNA gyrase and DNA topoisomerase IV from Escherichia coli and Staphylococcus aureus as well as the effect of potassium and sodium glutamate on the activity of these enzymes. The inhibitory concns. of the aminocoumarins were detd. in gyrase supercoiling assays and topoisomerase IV decatenation assays. Both subunits of S. aureus topoisomerase IV were purified as His-Tag proteins in E. coli. The MIC was tested in vivo for the control organisms E. coli ATCC 25922 and S. aureus ATCC 29213. DNA gyrase is the primary target in vitro of all investigated aminocoumarins. With the exception of simocyclinone D8, all other aminocoumarins inhibited S. aureus gyrase on av. 6-fold more effectively than E. coli gyrase. Potassium glutamate is essential for the activity of S. aureus gyrase and increases the sensitivity of E. coli gyrase to aminocoumarins ≥10-fold. The antibacterial activity of the tested compds. mirrored their relative activities against topoisomerases. The study provides insights about the substituents that are important for the inhibitory activity of aminocoumarins against the target enzymes, which will facilitate the rational design of improved antibiotics.
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    78. 78
      Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS. Infect. Dis. 2015, 1, 4– 41,  DOI: 10.1021/id500013t
      There is no corresponding record for this reference.
    79. 79
      Duma, R. J.; Warner, J. F. In Vitro Activity of Coumermycin A1 Against Mycobacterium tuberculosis var. hominis. Appl. Microbiol. 1969, 18, 404– 405,  DOI: 10.1128/am.18.3.404-405.1969
      There is no corresponding record for this reference.
    80. 80
      Broeck, A. V.; McEwen, A. G.; Chebaro, Y.; Potier, N.; Lamour, V. Structural Basis for DNA Gyrase Interaction with Coumermycin A1. J. Med. Chem. 2019, 62, 4225– 4231,  DOI: 10.1021/acs.jmedchem.8b01928
      There is no corresponding record for this reference.
    81. 81
      Gl, B.; Rajput, R.; Gupta, M.; Dahiya, P.; Thakur, J. K.; Bhatnagar, R.; Grover, A. Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis. Biochem. J. 2020, 477, 4167– 4190,  DOI: 10.1042/BCJ20200462
      81
      Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
      Gl Balasubramani; Rajput Rinky; Grover Abhinav; Gupta Manish; Bhatnagar Rakesh; Dahiya Pradeep; Thakur Jitendra K; Bhatnagar Rakesh
      The Biochemical journal (2020), 477 (21), 4167-4190 ISSN:.
      Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening the drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a potent binder of MtbGyrB47. Furthermore, ATPase, and DNA supercoiling assays exhibited an IC50 values of 2.1-4.7 μM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 and 12 μM were observed for epirubicin and echinacoside, respectively, against Mtb. Our findings indicate that echinacoside and epirubicin targets mycobacterial DNA gyrase, inhibit its catalytic cycle, and retard mycobacterium growth. Further, these compounds exhibit potential scaffolds for optimizing novel anti-mycobacterial agents that can act on drug-resistant strains.
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    82. 82
      Sherer, B. A.; Hull, K.; Green, O.; Basarab, G.; Hauck, S.; Hill, P.; Loch, J. T., 3rd.; Mullen, G.; Bist, S.; Bryant, J.; Boriack-Sjodin, A.; Read, J.; DeGrace, N.; Uria-Nickelsen, M.; Illingworth, R. N.; Eakin, A. E. Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy. Bioorg. Med. Chem. Lett. 2011, 21, 7416– 7420,  DOI: 10.1016/j.bmcl.2011.10.010
      82
      Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy
      Sherer, Brian A.; Hull, Kenneth; Green, Oluyinka; Basarab, Gregory; Hauck, Sheila; Hill, Pamela; Loch, James T., III; Mullen, George; Bist, Shanta; Bryant, Joanna; Boriack-Sjodin, Ann; Read, Jon; DeGrace, Nancy; Uria-Nickelsen, Maria; Illingworth, Ruth N.; Eakin, Ann E.
      Bioorganic & Medicinal Chemistry Letters (2011), 21 (24), 7416-7420CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochem. activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the mol. resulted in pyrrolamides with improved cellular activity and in vivo efficacy.
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    83. 83
      Durcik, M.; Nyerges, Á.; Skok, Ž.; Skledar, D. G.; Trontelj, J.; Zidar, N.; Ilaš, J.; Zega, A.; Cruz, C. D.; Tammela, P.; Welin, M.; Kimbung, Y. R.; Focht, D.; Benek, O.; Révész, T.; Draskovits, G.; Szili, PÉ; Daruka, L.; Pál, C.; Kikelj, D.; Mašič, L. P.; Tomašič, T. New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens. Eur. J. Med. Chem. 2021, 213, 113200  DOI: 10.1016/j.ejmech.2021.113200
      83
      New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens
      Durcik, Martina; Nyerges, Akos; Skok, Ziga; Skledar, Darja Gramec; Trontelj, Jurij; Zidar, Nace; Ilas, Janez; Zega, Anamarija; Cruz, Cristina D.; Tammela, Paivi; Welin, Martin; Kimbung, Yengo R.; Focht, Dorota; Benek, Ondrej; Revesz, Tamas; Draskovits, Gabor; Szili, Petra Eva; Daruka, Lejla; Pal, Csaba; Kikelj, Danijel; Masic, Lucija Peterlin; Tomasic, Tihomir
      European Journal of Medicinal Chemistry (2021), 213 (), 113200CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Here, the design and structure-activity relationship anal. of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens were reported. For inhibitor I•HCl (R = 2-(morpholin-4-yl)ethyl), a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compds. The best inhibitor, I [R = thiophen-3-yl-Me (II)], does not show any in vitro cytotoxicity and has excellent potency against Gram-pos. (MICs: range, 0.0078-0.0625μg/mL) and Gram-neg. pathogens (MICs: range, 1-2μg/mL). Furthermore, II inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, it was expected that structural derivs. of II will represent a step toward clin. efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.
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    84. 84
      Mesleh, M. F.; Cross, J. B.; Zhang, J.; Kahmann, J.; Andersen, O. A.; Barker, J.; Cheng, R. K.; Felicetti, B.; Wood, M.; Hadfield, A. T.; Scheich, C.; Moy, T. I.; Yang, Q.; Shotwell, J.; Nguyen, K.; Lippa, B.; Dolle, R.; Ryan, M. D. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Bioorg. Med. Chem. Lett. 2016, 26, 1314– 1318,  DOI: 10.1016/j.bmcl.2016.01.009
      There is no corresponding record for this reference.
    85. 85
      Ushiyama, F.; Amada, H.; Takeuchi, T.; Tanaka-Yamamoto, N.; Kanazawa, H.; Nakano, K.; Mima, M.; Masuko, A.; Takata, I.; Hitaka, K.; Iwamoto, K.; Sugiyama, H.; Ohtake, N. Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation. ACS Omega 2022, 5, 10145– 10159,  DOI: 10.1021/acsomega.0c00865
      There is no corresponding record for this reference.
    86. 86
      Skok, Ž.; Barančoková, M.; Benek, O.; Cruz, C. D.; Tammela, P.; Tomašič, T.; Zidar, N.; Mašič, L. P.; Zega, A.; Stevenson, C. E. M.; Mundy, J. E. A.; Lawson, D. M.; Maxwell, A.; Kikelj, D.; Ilaš, J. Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors. ACS Med. Chem. Lett. 2020, 11, 2433– 2440,  DOI: 10.1021/acsmedchemlett.0c00416
      86
      Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors
      Skok, Ziga; Barancokova, Michaela; Benek, Ondrej; Cruz, Cristina Durante; Tammela, Paivi; Tomasic, Tihomir; Zidar, Nace; Masic, Lucija Peterlin; Zega, Anamarija; Stevenson, Clare E. M.; Mundy, Julia E. A.; Lawson, David M.; Maxwell, Anthony; Kikelj, Danijel; Ilas, Janez
      ACS Medicinal Chemistry Letters (2020), 11 (12), 2433-2440CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymic activity, we systematically explored the chem. space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compds. with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compd. 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compd. 15a, with a low mol. wt. of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13μM), and efflux impaired E. coli strain (MIC = 0.78μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-neg. bacteria.
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    87. 87
      Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J. Med. Chem. 2012, 55, 6413– 6426,  DOI: 10.1021/jm300395d
      87
      Structure-Based Discovery of Substituted 4,5'-Bithiazoles as Novel DNA Gyrase Inhibitors
      Brvar, Matjaz; Perdih, Andrej; Renko, Miha; Anderluh, Gregor; Turk, Dusan; Solmajer, Tom
      Journal of Medicinal Chemistry (2012), 55 (14), 6413-6426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N2-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallog., confirming our initial in silico binding model. Furthermore, the high resoln. of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptF2ns78%253D&md5=3701c7c3442de99bcaf8e76c51933991
    88. 88
      Manchester, J. I.; Dussault, D. D.; Rose, J. A.; Boriack-Sjodin, P. A.; Uria-Nickelsen, M.; Ioannidis, G.; Bist, S.; Fleming, P.; Hull, K. G. Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV. Bioorg. Med. Chem. Lett. 2012, 22, 5150– 5156,  DOI: 10.1016/j.bmcl.2012.05.128
      88
      Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV
      Manchester, John I.; Dussault, Daemian D.; Rose, Jonathan A.; Boriack-Sjodin, P. Ann; Uria-Nickelsen, Maria; Ioannidis, Georgine; Bist, Shanta; Fleming, Paul; Hull, Kenneth G.
      Bioorganic & Medicinal Chemistry Letters (2012), 22 (15), 5150-5156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The discovery and optimization of a series of bacterial topoisomerase inhibitors, e.g., I, is disclosed. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and phys. property optimization. Synthesis of fewer than a dozen compds. was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus at compd. concns. of 1.56 μM. These compds. simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concns., reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOqt7bL&md5=7c2e42ef7a21c7805736065e84d86a49
    89. 89
      Gross, C. H.; Parsons, J. D.; Grossman, T. H.; Charifson, P. S.; Bellon, S.; Jernee, J.; Dwyer, M.; Chambers, S. P.; Markland, W.; Botfield, M.; Raybuck, S. A. Active–site residues of Escherichia coli DNA gyrase required in coupling ATP hydrolysis to DNA supercoiling and amino acid substitutions leading to novobiocin resistance. Antimicrob. Agents Chemother. 2003, 47, 1037– 1046,  DOI: 10.1128/AAC.47.3.1037-1046.2003
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.4c00511.

    • Hit compound cytotoxicity against Caco-2 cells; cells were incubated with different concentrations of compounds (1, 2, 3, 8, 11, 14, G24, and G26) for 24 h and viability measured by MTT assay; all-atom RMSD plots for MD simulations of M. tuberculosis GyrB:inhibitor complexes; per-residue analysis of inhibitor:GyrB interactions; hydrogen bond interactions of known ATPase inhibitors with Asp79 in the M. smegmatis DNA gyrase ATP binding site; hits and leads obtained from three different virtual screening methods; previously characterized compounds identified from virtual similarity screening; details of fit parameters for IC50 determinations; hydrogen bonding of most active compounds (R-stereomers) to GyrB Asp79; and calculated binding free energies for binding of compounds 8, 11, and 14 to the wild type and mutant (D79A) GyrB subunits (PDF)


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