Tuberculosis (TB) is one of the leading infectious diseases worldwide even with the ravaging COVID-19 pandemic in recent times. This mandated further search and exploration of more possible anti-TB drug candidates against M. tuberculosis strains. As an extension of our previous work on the homology modeled cytochrome b subunit of the bc1 complex (QcrB) of Mycobacterium tuberculosis, an in-silico design was carried out in order to further explore more newly potential anti-TB compounds. Ligand 26 was selected as the lead template (scaffold A) based on our previous docking results and its less bulky structure. Successively, eight (8) new ligands (A1-A8) were designed with better binding affinities in comparison to the scaffold template (-6.8 kcal/mol) and isoniazid standard drug (-6.00 kcal/mol) respectively. In addition, three (3) designed ligands namely, A6, A2, and A7 with higher binding affinities were validated via ADME and toxicity prediction analysis, and the results showed zero violations of Lipinski rules with similar bioavailability, and high rate in gastrointestinal absorption, while toxicity parameters such as carcinogenicity and cytotoxicity were all predicted as non-toxic (inactiveness). The designed IPA compounds in the present study could serve as a promising gateway that could help the medicinal and synthetic chemist in the exploration of a new set of derivatives as anti-TB agents. Therefore, this research strongly recommends further experimental consideration of the newly designed IPA compounds through synthesis, in-vitro and in-vivo studies to validate the theoretical findings.
Keywords: Binding affinity; Hydrogen bond; In-silico design; Molecular interactions; Pharmacokinetics; Tuberculosis.
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