Targeting Mycobacterium tuberculosis InhA with Phytochemicals: Insights from Molecular Docking and Dynamics Simulations

The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains has rendered many frontline antituberculosis agents ineffective, necessitating the urgent identification of novel therapeutic targets. One of the critical enzymes in Mtb lipid metabolism is enoyl-acyl carrier protein reductase (InhA), which catalyzes the NADH-dependent reduction of 2-trans-enoyl-ACP within the mycolic acid biosynthetic pathway. Inhibiting InhA with drugs blocks mycolic acid production, weakening the bacterial cell wall, disturbing metabolism, and ultimately lowering Mtb survival. Despite the existence of clinically approved InhA targeting agents, their therapeutic efficacy against drug-resistant Mtb strains is suboptimal, underscoring the necessity of identifying alternative inhibitors. Natural products, particularly phytochemicals derived from medicinal plants and herbs, represent a vast reservoir of structurally diverse bioactive molecules with potential antimicrobial properties. In this study, a structure-based virtual screening approach integrating molecular docking and molecular dynamics (MD) simulations was employed to identify potent phytochemical inhibitors of InhA. Chryso-obtusin (-8.92 kcal/mol), Episesamin (-8.74 kcal/mol), Apohyoscine (-7.84 kcal/mol), and Norhyosine (-7.74 kcal/mol)-exhibiting high-affinity interactions with the enzyme’s cofactor-binding domain. Subsequent MD simulations elucidated their stability and mechanistic similarity to isoniazid-mediated inhibition. These findings highlight the potential of natural phytochemicals as promising inhibitors of enoyl-ACP reductase, providing a foundation for the development of alternative therapeutic strategies against TB, particularly in the context of drug-resistant strains.