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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Research Article

Early Blockage of Mycobacterium Tuberculosis Cell-wall Synthesis via EchA\6 Inhibition to Overcome Resistance Strain: Insights from Umbrella Sampling Simulations

Author(s): Rafee Habib Askandar, Farhad Sharifi, Sepideh Shayan, Helya Mohammadi, Arian Rahimi, Noeman Ardalan* and Heshw Farhad Mohammed

Volume 19, Issue 10, 2023

Published on: 27 June, 2023

Article ID: e140623218016 Pages: 16

DOI: 10.2174/1573407219666230614163801

Price: $65

Abstract

Background: Tuberculosis (TB) has long been the major infectious cause of mortality, ranking higher than HIV/AIDS as the most common cause of death from a single infectious agent worldwide. The EchA6 target of mycobacteria plays a vital role in synthesizing an important component of the mycobacterial outer membrane. The failure of TB treatment has prompted the investigation of novel anti-tubercular drugs.

Objective: This study was aimed at blockage of Mycobacterium tuberculosis cell-wall synthesis via EchA6 inhibition to overcome resistance strain.

Methods: Over 3,000,000 compounds and GSK951A (positive control) were investigated as the inhibitors in this study. The GROMACS molecular dynamic package was used to analyze the protein- inhibitor complex's conformational changes under constant temperature and pressure. Also, umbrella sampling (US) was used for free binding energy (ΔG) calculation.

Results: Four compounds were chosen for the docking investigation. According to the MD analysis, the studied inhibitors demonstrated good stability and flexibility. According to ΔG obtained from US, the ΔG of GSK951A, ZINC11815220, ZINC67770050, ZINC55048326, and ZINC89700914 were -6.14 kcal mol-1, -5.25 kcal mol-1, -10.19 kcal mol-1, -8.55 kcal mol-1, and -8.37 kcal mol-1, respectively.

Conclusion: In conclusion, ZINC67770050 is recommended for further study in the laboratory. This investigation is an important starting point for discovering anti-tubercular drugs using EchA6 inhibition.<.p>

Keywords: Tuberculosis, EchA6 inhibitor, molecular docking, molecular dynamics simulation, umbrella sampling, Mycobacterium tuberculosis.

Graphical Abstract
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