In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) continuously pose a major public health concern around the globe, with a mounting death toll of approximately 1.4 million in 2019. The reduced bioavailability, increased toxicity and resistance of several first-line and second-line anti-TB drugs such as isoniazid, ethionamide have necessitated the search for new medications. In this research, we have identified several novel chemical compounds with anti-TB properties using various computational tools like molecular docking analysis, drug-likeness evaluation, ADMET profiling, P450 site of metabolism prediction and molecular dynamics simulation study. This study involves fifty drug-like compounds with antibacterial activity that inhibit InhA and EthR involved in the synthesis of one of the major lipid components, mycolic acid, which is crucial for the viability of Mycobacterium tuberculosis. Among these fifty compounds, 3-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-N-(2-methylphenyl) piperidine-1-carboxamide (C22) and 5-(4-Ethyl-phenyl)-2-(1H-tetrazol-5-ylmethyl)-2H-tetrazole (C29) were found to pass the two-step molecular docking, P450 site of metabolism prediction and pharmacokinetics filtering analysis successfully. Their binding stability for target proteins have been evaluated through RMSD, RMSF, Radius of gyration analysis from 10 ns Molecular Dynamics Simulation (MDS) run. Our identified drugs could be a capable therapeutic for Tuberculosis drug discovery, having said that more in vitro and in vivo testing is required to justify their potential as novel drug and mode of action.