Natural phytocompounds physalin D, withaferin a and withanone target L-asparaginase of Mycobacterium tuberculosis: a molecular dynamics study

Abstract

Tuberculosis is a major infectious disease that is responsible for high mortality in humans. The reason for the global burden is the emergence of new antibiotic resistant strains of Mycobacteria that showed resistance against the currently given therapy. It is identified that the pathogen utilizes the L-asparaginase enzyme as a virulence factor for survival benefits inside the host. Therefore, L-asparaginase of Mycobacterium tuberculosis is a promising therapeutic drug target. In view of the light, the present study explores thirty phytocompounds from medicinal plants to determine the binding affinity in the catalytic site of L-asparaginase. The studies initiated with the construction of the 3 D structure of L-asparaginase using homology modeling. Using the robustness of molecular docking with binding energy cut-off value < −9.0 kcal/mol and 100 ns molecular dynamics simulations, three phytocompounds viz., Physalin D (−9.11 kcal/mol), Withanone (−9.45 kcal/mol) and Withaferin A (−9. 67 kcal/mol) showed strong binding potential compared to the product, L-aspartate (−5.87 kcal/mol). The active site residues identified are Thr 12, Asp 51, Ser 53, Thr 84, Asp 85, and Lys 157. Upon MD simulations, the phytocompounds and the product L-aspartate remain present in the same catalytic pocket of the enzyme. The RMSD, RMSF, radius of gyration and H-bond analysis of enzyme ligand complexes efficiently showed the stability of ligands at the docked site. Further, ADME studies distinctly demonstrate the potential of selected phytoconstituents as therapeutics. Thus, serve as safe and low-cost alternatives to chemical compounds to be used in combination therapy for treatment of tuberculosis.

Communicated by Ramaswamy H. Sarma

Keywords:

• L-asparaginase
• phytocompounds
• anti-microbials
• molecular dynamics simulations
• ADME studies

Acknowledgments

The support and the resources provided by ‘PARAM Shivay Facility’ under the National Supercomputing Mission, Government of India at the Indian Institute of Technology, Varanasi are gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the author(s).