Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors

DNA gyrase subunit B (GyrB) is an attractive drug target for the development of antibacterial agents with therapeutic potential. In the present study, computational studies based on pharmacophore modelling, atom-based QSAR, molecular docking, free binding energy calculation and dynamics simulation w...

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Bibliographic Details
Published in:	SAR and QSAR in environmental research Vol. 28; no. 4; pp. 275 - 296
Main Authors:	Azam, M. A., Thathan, J.
Format:	Journal Article
Language:	English
Published:	England Taylor & Francis 03-04-2017 Taylor & Francis Ltd
Subjects:	3D-QSAR Affinity Amino acids Anti-Infective Agents - chemistry Antibacterial agents Antiinfectives and antibacterials Binding energy Binding Sites Chemical compounds Computer applications Computer simulation Deoxyribonucleic acid DNA DNA Gyrase - chemistry DNA topoisomerase Drug Discovery Dynamics simulation Free energy GyrB High-throughput screening Hydrogen Bonding Hydrogen bonds in silico HTVS Inhibitors Mathematical analysis Mathematical models MM-GBSA Molecular docking Molecular Docking Simulation Molecular dynamics Molecular Dynamics Simulation Pharmacology Pyridines Quantitative Structure-Activity Relationship Residues Simulation Structure-activity relationships Thermodynamics Topoisomerase II Inhibitors - chemistry Urea Urea - analogs & derivatives Urea - chemistry GyrB 3D-QSAR in silico HTVS MM-GBSA Dynamics simulation
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Summary:	DNA gyrase subunit B (GyrB) is an attractive drug target for the development of antibacterial agents with therapeutic potential. In the present study, computational studies based on pharmacophore modelling, atom-based QSAR, molecular docking, free binding energy calculation and dynamics simulation were performed on a series of pyridine-3-carboxamide-6-yl-urea derivatives. A pharmacophore model using 49 molecules revealed structural and chemical features necessary for these molecules to inhibit GyrB. The best fitted model AADDR.13 was generated with a coefficient of determination (r²) of 0.918. This model was validated using test set molecules and had a good r² of 0.78. 3D contour maps generated by the 3D atom-based QSAR revealed the key structural features responsible for the GyrB inhibitory activity. Extra precision molecular docking showed hydrogen bond interactions with key amino acid residues of ATP-binding pocket, important for inhibitor binding. Further, binding free energy was calculated by the MM-GBSA rescoring approach to validate the binding affinity. A 10 ns MD simulation of inhibitor #47 showed the stability of the predicted binding conformations. We identified 10 virtual hits by in silico high-throughput screening. A few new molecules were also designed as potent GyrB inhibitors. The information obtained from these methodologies may be helpful to design novel inhibitors of GyrB.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1062-936X 1029-046X
DOI:	10.1080/1062936X.2017.1310131