Abstract
Tuberculosis is an ancient chronic disease caused by Mycobacterium tuberculosis (M. tuberculosis) and remains one of the leading causes of death worldwide. InhA, an enoyl-ACP reductase in M. tuberculosis, plays a crucial role in the biosynthesis of mycolic acids, essential constituents of the mycobacterial cell wall. Therefore, InhA enzyme has been considered as a promising target for the development of novel antitubercular drugs. In our previous molecular simulations, we investigated the interactions between InhA and a series of benzimidazole derivatives for the crystal structure of InhA (PDB ID: 6R9W) using ab initio fragment molecular orbital (FMO) calculations. To design highly effective benzimidazole derivatives as InhA inhibitors, we here extended our molecular simulations to other derivatives and highlighted key electronic-level interactions between InhA and these compounds. Indeed, we strategically modified substituents at three sites of the 2,3-dihydro-1H-indene ring of the most potent benzimidazole derivative, with the aim of facilitating hydrogen bond formation to InhA residues. A total of 24 compounds were rationally designed and virtually screened based on Lipinski's rule of five and toxicity predictions, ultimately obtaining nine promising candidate compounds. Using FMO calculations, specific interactions were elucidated between InhA and the compounds to highlight key interactions for achieving high binding affinity to InhA. Notably, the highest-affinity inhibitor exhibited strong hydrogen bond interactions with the backbones of Gln100, Ala157, and Ile215, as well as nicotinamide adenine dinucleotide of InhA. These findings provide valuable structural insights for designing novel benzimidazole derivatives with improved binding efficiency to InhA. Overall, our ab initio molecular simulations provide crucial insights for the rational design of more effective InhA inhibitors, potentially advancing tuberculosis chemotherapy.