Identification of potential anti-tubercular inhibitors through virtual screening, DFT, and molecular dynamics simulation studies

Tuberculosis (TB) continues to pose a significant threat to global health, a problem intensified by the rise of strains of Mycobacterium tuberculosis that resist multiple drugs. Identifying novel inhibitors against essential bacterial targets is critical for developing effective therapies. This research utilized computational techniques to discover new inhibitors targeting CYP121 enzymes of M. tuberculosis (PDB ID: 5IBG). We subjected a library of 37 compounds to a rigorous screening process including virtual screening, molecular docking, DFT calculations, ADMET profiling, and MD simulations. compound 19 showed the strongest binding interaction (MolDock score of -172.363) along with favourable pharmacological characteristics. Structural optimization yielded analogue 19c, which demonstrated improved score (MolDock score of -181.095) and greater stability during MD simulations, as indicated by reduced RMSD and RMSF values, persistent hydrogen bonds, and enhanced MM-GBSA binding energy. DFT investigations showed a narrower HOMO-LUMO gap for 19c, suggesting increased chemical reactivity. Additional analyses using non-covalent interaction (NCI-RDG) mapping and molecular electrostatic potential (MEP) profiling confirmed the existence of strong and well-defined interactions, along with favourable electrostatic complementarity inside the enzyme’s active site. The ADMET assessment further revealed desirable pharmacokinetic features, including good intestinal absorption and low toxicity risk. Analogue 19c exhibits improved stability, binding affinity, and pharmacokinetic properties, highlighting its promise as a potent CYP121 inhibitor. These findings support further experimental validation of 19c as a prospective anti-tubercular agent. • Lead Identification: Compound 19 was identified as a high-affinity inhibitor of M. tuberculosis IMPDH (MolDock score: -172.363 kcal/mol) through comprehensive virtual screening and molecular docking studies. • Analogue Optimization: Structural modification of compound 19 yielded analogue 19c, which demonstrated superior binding affinity (MolDock score: -181.095 kcal/mol) and enhanced predicted inhibitory potential. • Integrated Computational Approach: This study synergistically combined molecular docking, DFT calculations, ADMET profiling, and molecular dynamics simulations to rigorously evaluate and validate the identified leads. • Stability and Binding Confirmation: Molecular dynamics simulations over 135 ns confirmed the superior stability of the 19c protein complex, evidenced by low RMSD/RMSF values, sustained hydrogen bonding, and a favourable MM-GBSA binding free energy (-149.883 kcal/mol). • Promising Drug-Likeness: Analogue 19c exhibits excellent predicted pharmacokinetic properties, including high gastrointestinal absorption and a minimal toxicity profile, underscoring its potential as a novel anti-tubercular drug candidate.