Integrated quantum chemical and molecular dynamics studies of isoscopoletin against Mycobacterium tuberculosis...

Tuberculosis (TB) is a major global health issue worsened by drug-resistant isolates. This study presents a detailed in silico investigation of isoscopoletin by combining quantum-chemical calculations, pharmacokinetic profiling, molecular docking, and molecular dynamics simulations against the Mycobacterium tuberculosis target protein thymidylate kinase. Structural stability was established by geometry optimization using density functional theory (DFT) at the APFD/6-311+G(2d,p) level of theory. The optimized molecular geometry was used to obtain HOMO-LUMO energies, chemical reactivity descriptors and molecular electrostatic potential (MEP). Frontier molecular orbital analysis showed a small HOMO-LUMO energy gap of 4.3 eV, indicating high reactivity, while molecular electrostatic potential (MEP) mapping highlighted reactive nucleophilic and electrophilic regions. Topology analyses, such as ELF, LOL, RDG, NCI, frontier orbital analysis, and molecular electrostatic potential mapping, were all insightful for charge distribution and non-covalent interactions. Pharmacokinetic and ADMET profiling demonstrated favorable drug-likeness, with a TPSA of 59.67 Ų and a bioavailability score of 0.55. Molecular docking suggested strong binding affinity, which was further validated by 200 ns molecular dynamics simulations. The protein-ligand complex exhibited stable RMSD values ranging from 1.0 to 2.6 Å (average ≈ 1.8 Å) compared to the free protein (1.8-3.0 Å; average ≈ 2.4 Å), indicating enhanced stability upon ligand binding. RMSF analysis showed minimal residue fluctuations (0.05-0.20 nm), while the radius of gyration remained stable between 1.60 and 1.72 nm. Principal component analysis revealed that the first three components (PC1: 26.16%, PC2: 14.45%, PC3: 9.14%) accounted for 49.8% of the total motion, indicating coordinated and stable dynamics. These computational findings demonstrate that isoscopoletin exhibits favorable electronic properties, stable protein-ligand interactions, and good pharmacokinetic characteristics, supporting its application as an anti-tubercular drug.