Development of new potential Mycobacterium tuberculosis enoyl-ACP reductase inhibitors

It’s proposed the design of new potential tuberculosis InhA inhibitors by molecular modeling using molecular docking, dynamics , 3D-QSAR, pharmacophore modeling,and virtual screening approaches. In short, a series of diaryl ether derivatives were selected from literature as a model of direct InhA inhibitors. The highly- scored poses that each inhibitor assumes in the binding site of the holoenzyme (InhA-NADH) were identify by molecular docking. The inhibitor-InhA-NADH complexes were submitted to molecular dynamics in aqueous solution to identify the movements of the structures that form the binding site, as well as the influence of the solvent. Then, to identify which residues would be related to biological activity, 3D-QSAR models were built. The pharmacophore model was used for virtual screening in the ZINC database, where compound 1 was identified as a new hit. Finally, it was proposed a synthetic route and a series of derivatives containing different substituents in the phenyl ring