Exploring Withania somnifera derived natural products as promising inhibitors of Mycobacterium tuberculosis Pantothenate Kinase-PanK: An integrated in silico and in vitro approach

Abstract

Background: Tuberculosis remains a pervasive and enduring global health challenge, with the alarming rise of drug-resistant variants. Mycobacterium tuberculosis (M. tuberculosis), bacterium responsible for tuberculosis, deploys a complex arsenal of virulence factors to evade the host's immune defences. The quest for novel targets or compounds to combat drug-resistant M. tuberculosis strains is of paramount importance. PanK is an essential enzyme for Co-enzyme A (CoA) biosynthesis pathway, targeting inhibition of its activity by Withania somnifera phytochemicals may provide an effective therapeutic strategy against resistant strains.

Objective: The study aims to identify the potential of natural compounds derived from Withania somnifera as inhibitors of the PanK enzyme (novel target) in M. tuberculosis.

Methodology: In silico computational approach, includes steps-structure based virtual screening of 83 Withania compounds followed by molecular docking and dynamic simulations spanning 100 ns, to assess the binding affinity and stability between screen key compounds and PanK. In vitro anti-tuberculosis bioassays was also performed to validate the In silico experiments finding.

Result: Through in silico experiments, four key compounds of Withania somnifera were -Morkotin A, Rutin, Withaoxylactone, and 2,3-Dihydrowithanolide E were identified. They exhibited strong potential to inhibit PanK enzyme activity. The In silico as well as In vitro findings suggest that Withania somnifera-derived natural compounds could serve as effective candidates for targeting vital enzymes in M. tuberculosis.

Conclusion: Withania somnifera can be explored as valuable resource for developing novel drugs for PanK as a target to combat tuberculosis.

Keywords: Drug resistance; Pantothenate Kinase-PanK; Phytochemicals; Simulations; Tuberculosis.