MOLECULAR DOCKING STUDIES OF ISATIN-LINKED CHALCONE DERIVATIVES AS ANTI-TB DRUG CANDIDATES AND THEIR ADMET PREDICTION

Objective: Molecular docking studies were carried out on fifteen novel Isatin-linked chalcone derivatives to evaluate their potential as anti-tuberculosis drug candidates targeting NADH-Dependent 2-trans Enoyl–Acyl Carrier Protein Reductase (InhA). Methods: The compounds were designed in-silico and optimized using Molegro Virtual Docker (MVD) and AutoDock tools to target the InhA enzyme (PDB ID: 4QXM). Molecular docking simulations indicated that compounds 6-9 exhibited superior binding affinities (-10.5 kcal/mol) compared to the standard drugs Isoniazid (-6.1 kcal/mol) and NAD+ (-10.3 kcal/mol). Results: Analysis of protein-ligand interactions demonstrated that the most active compounds formed stable hydrogen bonds with key residues PHE-41, THR-39, and LEU-63 in the InhA binding pocket. ADMET predictions indicated favorable drug-like properties for all synthesized compounds, with acceptable molecular weights (350-450 Da), optimal lipophilicity (LogP< 5), and high gastrointestinal absorption rates. The compounds showed compliance with Lipinski’s rule of five and exhibited blood-brain barrier permeability. Conclusion: The direct targeting of InhA by these chalcone derivatives, independent of KatG activation, indicates potential effectiveness against drug-resistant Mycobacterium tuberculosis strains.