Computational Discovery of Phytochemicals Targeting InhA of Mycobacterium tuberculosis: Insights from Molecular Docking, MMGBSA, ADME Profiling, and Molecular Dynamics Simulations

Abstract

Tuberculosis (TB) is one of the most serious global health issues, with the increasing number of multidrug-resistant TB cases emphasizing the need for new therapeutic approaches. Phytochemicals, with their diverse structures and favorable safety profiles, are a largely unexplored area for anti-TB drug development. An ethnobotanical study and literature analysis identified 310 medicinal plants traditionally used to treat respiratory infections, which produced 4,087 phytochemicals. Their structures were obtained from PubChem or drawn using ChemDraw, and pharmacokinetic properties were analyzed using QikProp. Enoyl-acyl carrier protein reductase (InhA, PDB ID: 4TRO), an important enzyme involved in mycolic acid biosynthesis, was selected as the target protein. Molecular docking was performed using Glide, followed by MMGBSA calculations, and the best hits were validated by 300 ns molecular dynamics simulations using the GROMACS pipeline. Binding affinities showed that four phytochemicals, namely Patuletin, skimmin, flavonol- 3-O-D-glycoside, and salicin, had significantly higher binding affinity scores (-10.06 to -8.82 kcal/mol) than first-line anti-TB drugs isoniazid (-6.35 kcal/mol) and pyrazinamide (-4.22 kcal/mol). Patuletin and skimmin had MM-GBSA binding affinity scores of -74.89 and -71.76 kcal/mol, respectively. MD simulations of the top 3 compounds and control showed that the protein-ligand complexes were stable, as indicated by the RMSD, RMSF, Radius of gyration, SASA, and HBONDS. Patuletin and Skimmin demonstrated strong binding affinity and structural stability against the InhA enzyme (PDB: 4TRO), indicating their potential as promising lead compounds for anti-tuberculosis effects. Derived from ethnomedicinal plants, these phytochemicals not only target key mycobacterial pathways but may also offer hepatoprotective and immunomodulatory benefits. The findings support the exploration of plant-derived compounds as safer and effective alternatives or adjuncts to conventional anti-TB therapies. The combination of virtual screening, ADME studies, and MD simulations enabled the identification of phytochemicals with promising interactions toward InhA, an established anti-TB target. The findings are based solely on computational analysis and should be interpreted as preliminary evidence of target engagement rather than confirmed inhibitory activity or therapeutic efficacy. These natural products may serve as potential lead compounds for further anti-tubercular drug discovery, warranting subsequent biochemical, cellular, and in vivo validation to establish their inhibitory potential, safety, and pharmacological effectiveness.