In silico identification of novel chemical compounds with antituberculosis activity for the inhibition of InhA and EthR proteins from Mycobacterium tuberculosis

Halder, Sajal Kumar; Elma, Fatiha

Tuberculosis (TB) continuously poses a major public health concern around the globe, with a mounting death toll of approximately 1.4 million in 2019. Reduced bioavailability, elevated toxicity, increased side effects, and resistance of multiple first-line and second-line TB medications, including isoniazid, ethionamide necessitate studies of new drugs. The method of computational biology and bioinformatics approach allows virtual screening of a large number of drugs, reduces growing side effects of medications, and predicts potential drug resistance over time. In this study, we have analyzed fifty small molecules with antituberculosis properties using in silico approach including molecular docking, drug-likeness assessment, ADMET (absorption, distribution, metabolism, excretion, toxicity) profile evaluation, P450 site of metabolism prediction, and molecular dynamics simulation. Among those 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 analysis successfully. Their binding stability for target proteins has been evaluated through root mean square deviation and root mean square fluctuation, Radius of gyration analysis from 10 ns Molecular Dynamics Simulation (MDS). Our identified drugs (C22 and C29) performed better than the control drugs (Isoniazid, Ethionamide) regarding binding affinity and molecular stability with the regulatory proteins (InhA, EthR) of Mycobacterium tuberculosis. The study proposed these compounds as effective therapeutic agents for Tuberculosis drug discovery, but further in vitro and in vivo testing are needed to substantiate their potential as novel drugs and modes of action.