Virtual screening assisted discovery of novel natural products to inhibit the catalytic mechanism of Mycobacterium tuberculosis InhA

Abstract

The pandemic prevalence of tuberculosis (TB) caused by increasing drug-resistant Mycobacterium tuberculosis (Mtb) strains has posed severe global health threats. The resistance developed against conventional drugs within Mtb strains has complicated TB management and common therapeutic approaches. As a promising target for alternative antimicrobials, the mycobacterial InhA has drawn much attention for its vital role in the mycolic acid (MA) biosynthesis pathway and mutagenesis. Through this work, virtual screening assisted discovery of novel chemotypes from three natural product databases (Specs, Enamine and NPACT-SANDB) were implemented to hinder the catalytic mechanism of Mtb InhA. Five potential hit molecules, of which one from Specs and two from each Enamine and NPACT-SANDB, are shortlisted as potential alternative molecules with favourable pharmacokinetic properties. The resulting hits stability in the docked confirmation with Mtb InhA were evaluated through molecular dynamics simulation (MDS) along with principal component analysis (PCA), followed by hits-InhA binding free energy calculation using molecular mechanics Poisson‐Boltzmann surface area (MM-PBSA). The structural stability results revealed the stable interactions between the hit molecules and active site residues that are critical for upholding the catalytic activity. The selected hit molecules had desirable inhibition potential, among them, Enamine 57340 showed higher binding affinity and Enamine 57294, NPACT 21742 and NPACT 62 were showing moderate binding affinities and of Specs 1845 with weaker binding affinity. The studied potential lead molecule Enamine 57340 can be considered for further biological activities to confirm the promising therapeutic ability of against TB.