title: Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors.
abstract: 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.
authors.affiliation: a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Tamil Nadu , India.
authors.forename: M A
authors.initials: MA
authors.lastname: Azam
authors.affiliation: a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Tamil Nadu , India.
authors.forename: J
authors.initials: J
authors.lastname: Thathan
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry*; D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry*; D055808:Drug Discovery; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011725:Pyridines; D021281:Quantitative Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D000890:Anti-Infective Agents; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D014508:Urea; D027081:DNA Gyrase
keywords: 3D-QSAR; Dynamics simulation; GyrB; MM-GBSA; in silico HTVS