Discovery of Potential Inhibitors of Mycobacterium tuberculosis EthR Using Structure and Ligand Based in silico Approaches

Abstract:

Aim and Background: Mycobacterium tuberculosis (TB) remains the leading cause of human death posing one of the most serious threats to public health around the world. New strategies need to be developed to combat the growing danger by multidrug resistance. The present study aims to screen three different compounds inhibiting the binding pocket of Regulatory Repressor Protein EthR of Mycobacterium tuberculosis. In this study we performed pharmacophore modeling based virtual screening to identify the potential inhibitors against EthR of Mycobacterium tuberculosis. Based on the binding energy and hydrogen bond interactions three compounds were selected as potential inhibitors. Materials and Methods: Structure of EthR protein (PDB ID: 5NZ0) was retrieved from pdb databank. Further, we retrieved ligands from ZINC database (ZINC223412753, ZINC030691754, ZINC170602403). Next, Computational screening, Docking studies and Molecular dynamic simulations were performed to validate the stability of the complexes. Results: The molecular docking showed that all ligands interact with EthR protein of Mycobacteriam. Further, molecular dynamics simulation showed that ligand ZINC223412753 form comparatively more stable complex with EthR. Results showed that all the three ligands could be a potential inhibitor of EthR. Conclusion: These compounds can serve as a starting point in rational design of selective potent inhibitors against Mycobacterium tuberculosis.

Keywords: Mycobacterium tuberculosis, Pharmacophore, Molecular Docking, Virtual Screening, Molecular Dynamic Simulations, Inhibitors.