Cell wall permeability assisted virtual screening to identify potential direct InhA inhibitors of Mycobacterium tuberculosis and their biological evaluation.

The arising cases of isoniazid-resistance have motivated research interests toward new class of molecules known as direct InhA inhibitors. Here, a combine approach of shape-based pharmacophore and descriptor-based 2D QSAR was used to identify the potential direct InhA inhibitors. The approach is duly assisted with in vitro testing and molecular dynamics simulations. A combination of empirical parameters was derived to use as a filter for cell wall permeability while 2D QSAR was used as another filter to predict the biological activity. Both filters were applied to prioritize the molecules for biological evaluation against anti-TB activity. It led to 6 potential molecules which showed > 90% inhibition of H37Rv strain of Mycobacterium tuberculosis in BACTEC assay. Further, MMGBSA binding free energy of identified molecules was compared with available highly potent molecule, 5-hexyl-2-(2-methylphenoxy) phenol (IC = 5nM) using molecular dynamics simulations. It showed two molecules with comparatively higher affinity toward InhA as compared to potent molecule. It indicated the candidature of identified molecules to be further considered in anti-TB drug development pipeline.