Molecular modelling assisted identification of novel Benzoxazole derivatives as hit molecules targeting Mycobacterial Membrane Protein Large 3 (MmpL3).

MmpL3 protein plays a vital role in cell wall synthesis in Mycobacterium. Novel benzoxazole carboxamide derivatives were designed to inhibit cell wall formation by targeting the MmpL3 and combat tuberculosis. Fourteen benzoxazole carboxamide derivatives (BXZ-I to BXZ-XIV) were synthesised, and their structures were confirmed using both experimental and computational methods. Techniques such as molecular docking, ADME, toxicity prediction, deep learning-based docking, and molecular dynamics simulation were used to analyse these compounds. Molecules with promising antimycobacterial activity were selected for MDS, MM-GBSA, and FEP analyses. BXZ-IX and BXZ-XIV exhibited potent activity against Mycobacterium smegmatis, with a minimum inhibitory concentration (MIC) of 15.62 μg/mL, compared with SQ109 (standard MmpL3 inhibitor), which had an MIC of 10.0 μg/mL. Overall, ten of the selected benzoxazole compounds significantly inhibited the growth of M. smegmatis, with MICs ranging from 15.62 to 62.5 μg/mL in laboratory tests, demonstrating greater effectiveness against the MmpL3 protein.