Molecular docking studies for investigating and evaluating some active compounds as potent anti-tubercular agents against InhA Inhibitors: In-Silico design, MD Simulation, DFT and Pharmacokinetics studies

The ongoing global challenge posed by drug-resistant strains of Mycobacterium tuberculosis underscores the urgent need for novel therapeutic strategies. In this study, a comprehensive in silico approach was utilized to design, analyse, and evaluate a series of small-molecule inhibitors targeting the InhA enzyme, a critical component in mycolic acid biosynthesis. A total of 47 ligands were analysed using molecular docking, quantum chemical calculations, Molecular dynamics simulation, and ADMET profiling. Compounds 10, 12, and 14 exhibited superior binding affinities compared to reference drugs, with compound 14 emerging as the most promising based on MolDock scores, MM/GBSA binding energy (-70.08 kcal/mol), and dynamic stability from a 250 ns molecular dynamics (MD) simulation. Principal component analysis confirmed enhanced conformational stability for compound 14. Based on its favourable binding and non-toxic ADMET profile, compound 14 was chosen as a template compound for the design of two new derivatives. These analogues demonstrated improved docking scores (-132.579 and − 125.894 kcal/mol), high intestinal absorption (> 88%), and no predicted toxicity. The findings support compound 14 and its derivatives as viable InhA inhibitors for further preclinical development in TB therapy.