High-throughput virtual screening, ADME analysis, and estimation of MM/GBSA binding-free energies of azoles as potential inhibitors of Mycobacterium tuberculosis H37Rv.

Isoniazid, also known as isonicotinyl hydrazide (INH), was used as a frontline drug to treat Mycobacterium tuberculosis. The in silico virtual screening is used to identify the effective inhibitor for CYP 121 of M. tuberculosis. Nearly, 10,000 triazole compounds from various databases have been virtually screened against CYP121 by using the module Glide. A total of 15 molecules with a better docking score compared to marketed drugs and cocrystal ligand were chosen for the MM/GBSA study to recheck the binding affinity. A total of five hit molecules which show significant binding-free energies were chosen for QikProp studies. The triazole molecules which contain 3-benzaimidine moiety interact with a heme cofactor and active site residues of CYP121. These protein-ligand complexes were taken to calculate the potential binding region of the ligand in the receptor using the solvent accessible surface area (SASA). The amino residues Phe168, Val228, Gln385, Trp182, Asp185, Val83, and heme 401 cofactor of the target protein are the important binding residues with the ligands. The in silico ADME studies for the ligand dataset are calculated to determine the druggability of the molecules.