Computational Investigation of Phytochemicals Targeting Isocitrate Lyase to Inhibit Mycobacterium tuberculosis

Abstract

Introduction: The global burden of tuberculosis (TB) remains a major concern for society that is worsening day by day with the emergence of drug-resistant TB as well as risks associated with latent TB. Isocitrate lyase (ICL) has been shown as a potential target that plays a role in the la-tent/dormant stage of M. tuberculosis. Several inhibitors against ICL have been designed and tested, which have various side effects.

Methodology: This study focuses on the phytochemicals from plant extracts, which have anti-tuber-cular properties. A total of 1413 phytochemicals were virtually screened against ICL to identify the promising therapeutic compounds. The top four lead phytochemicals were selected based on their binding energy and subjected to redocking and intermolecular interaction analysis. These results were further validated through 100 ns MD simulation to check the stability of these complexes. The find-ings of these complexes were compared to the reference compound VGX.

Results: The top selected compound viz., Allantoin, Gallic acid, Citric acid, and 3,5-Dihydroxyben-zoic acid from virtual screening result displayed better docking score ranging from -8 kcal/mol to -7.2 kcal/mol than the reference compound VGX (-7.5 kcal/mol). Moreover, during the MD simula-tion analysis, gallic acid exhibited greater stability compared to all other compounds, including the reference compound.

Conclusion: Among selected phytochemicals, gallic acid exhibited highest stability and binding af-finity within the active site of ICL as compared to previously identified compounds, which suggests that it is as potential candidate against ICL. That can be used for further in vitro and in vivo studies to evaluate its effectiveness against TB.

Keywords: Tuberculosis; gallic acid.; isocitrate lyase; molecular dynamics simulation; phytochemicals; virtual screening.