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Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors.
SAR QSAR Environ Res. 2017 Apr; 28(4):275-296.SQ

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.

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Authors+Show Affiliations

Azam MA
a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Tamil Nadu , India.
Thathan J
a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Tamil Nadu , India.

MeSH

Anti-Infective AgentsBinding SitesDNA GyraseDrug DiscoveryHydrogen BondingMolecular Docking SimulationMolecular Dynamics SimulationPyridinesQuantitative Structure-Activity RelationshipTopoisomerase II InhibitorsUrea

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28399673

Citation

Azam, M A., and J Thathan. "Pharmacophore Generation, Atom-based 3D-QSAR and Molecular Dynamics Simulation Analyses of Pyridine-3-carboxamide-6-yl-urea Analogues as Potential Gyrase B Inhibitors." SAR and QSAR in Environmental Research, vol. 28, no. 4, 2017, pp. 275-296.
Azam MA, Thathan J. Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors. SAR QSAR Environ Res. 2017;28(4):275-296.
Azam, M. A., & Thathan, J. (2017). Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors. SAR and QSAR in Environmental Research, 28(4), 275-296. https://doi.org/10.1080/1062936X.2017.1310131
Azam MA, Thathan J. Pharmacophore Generation, Atom-based 3D-QSAR and Molecular Dynamics Simulation Analyses of Pyridine-3-carboxamide-6-yl-urea Analogues as Potential Gyrase B Inhibitors. SAR QSAR Environ Res. 2017;28(4):275-296. PubMed PMID: 28399673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors. AU - Azam,M A, AU - Thathan,J, Y1 - 2017/04/12/ PY - 2017/4/13/pubmed PY - 2017/12/1/medline PY - 2017/4/13/entrez KW - 3D-QSAR KW - Dynamics simulation KW - GyrB KW - MM-GBSA KW - in silico HTVS SP - 275 EP - 296 JF - SAR and QSAR in environmental research JO - SAR QSAR Environ Res VL - 28 IS - 4 N2 - 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. SN - 1029-046X UR - https://www.unboundmedicine.com/medline/citation/28399673/Pharmacophore_generation_atom_based_3D_QSAR_and_molecular_dynamics_simulation_analyses_of_pyridine_3_carboxamide_6_yl_urea_analogues_as_potential_gyrase_B_inhibitors_ L2 - https://www.tandfonline.com/doi/full/10.1080/1062936X.2017.1310131 DB - PRIME DP - Unbound Medicine ER -
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