In Silico Screening of Azetidinone-Substituted Benzotriazole Derivatives as Promising Anti-Tubercular Agents Targeting CYP125 Enzyme

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health challenge, particularly due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains.There is an urgent need for novel therapeutic agents targeting essential mycobacterial enzymes.Objective: This study aimed to evaluate eight novel azetidinone-substituted benzotriazole derivatives as potential inhibitors of Mtb CYP125, a key enzyme involved in bacterial survival, using computational approaches.Methods: Molecular docking was performed using AutoDock Vina to assess binding affinities against the CYP125 enzyme (PDB ID: 7QKE).ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties were predicted using computational tools to evaluate drug-likeness and safety profiles. Results:The docking results demonstrated strong binding affinities (-8.8 to -10.1 kcal/mol), outperforming the standard drug rifampicin (-6.7 kcal/mol).Compounds 1, 2, and 8 exhibited the highest binding scores (-10.1, -10.0, and -10.1 kcal/mol, respectively), forming stable interactions with key residues (ARG274, CYS172, TYR208) through hydrogen bonds, -stacking, and hydrophobic contacts.ADMET analysis revealed favorable pharmacokinetics, including high intestinal absorption (87.5-97.5%)and compliance with Lipinski's Rule of Five.Compound 2 was identified as a non-mutagenic lead candidate with optimal logP (2.03) and 96.7% absorption, though its low solubility warrants further optimization. Conclusion:The benzotriazole derivatives, particularly Compounds 1, 2, and 8, show promising potential as anti-TB agents against resistant strains.Future studies should focus on in vitro validation, molecular dynamics simulations, and structural modifications to enhance solubility and reduce toxicity.