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

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. This study was aimed at blockage of Mycobacterium tuberculosis cell-wall synthesis via EchA6 inhibition to overcome resistance strain. 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 (∆G) calculation. Four compounds were chosen for the docking investigation. According to the MD analysis, the studied inhibitors demonstrated good stability and flexibility. According to ∆G obtained from US, the ∆G 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. 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.