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

• Published in: SAR and QSAR in environmental research 2017-04, Vol.28 (4), p.275-296
• Main Authors: Azam, M. A., Thathan, J.
• Format: Article
• Language: English
• 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
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2017.1310131

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.