Identification of new benzamide inhibitor against <i>α</i>-subunit of tryptophan synthase from <i>Mycobacterium tuberculosis</i> through structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations

<p>Multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis has emerged as global health threat, causing millions of deaths worldwide. Identification of new drug candidates for tuberculosis (TB) by targeting novel and less explored protein targets will be invaluable for antituberculosis drug discovery. We performed structure-based virtual screening of eMolecules database against a homology model of relatively unexplored protein target: the <i>α</i>-subunit of tryptophan synthase (<i>α</i>-TRPS) from <i>Mycobacterium tuberculosis</i> essential for bacterial survival. Based on physiochemical properties analysis and molecular docking, the seven candidate compounds were selected and evaluated through whole cell-based activity against the H37Rv strain of <i>M. tuberculosis</i>. A new Benzamide inhibitor against <i>α</i>-subunit of tryptophan synthase (<i>α</i>-TRPS) from <i>M. tuberculosis</i> has been identified causing 100% growth inhibition at 25 μg/ml and visible bactericidal activity at 6 μg/ml. This benzamide inhibitor displayed a good predicted binding score (−48.24 kcal/mol) with the <i>α</i>-TRPS binding pocket and has logP value (2.95) comparable to Rifampicin. Further refinement of docking results and evaluation of inhibitor-protein complex stability were investigated through Molecular dynamic (MD) simulations studies. Following MD simulations, Root mean square deviation, Root mean square fluctuation and secondary structure analysis confirmed that protein did not unfold and ligand stayed inside the active pocket of protein during the explored time scale. This identified benzamide inhibitor against the <i>α</i>-subunit of TRPS from <i>M. tuberculosis</i> could be considered as candidate for drug discovery against TB and will be further evaluated for enzyme-based inhibition in future studies.</p>