Integrative Molecular Docking and Dynamics Simulation for Repurposing FDA-Approved Drugs Against MGMT-Mediated Temozolomide Resistance in Glioblastoma

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor, where resistance to temozolomide (TMZ) is predominantly driven by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). This study aimed to repurpose FDA-approved drugs as MGMT inhibitors through a comprehensive in silico approach to enhance TMZ efficacy. Methods: The MGMT crystal structure (PDB ID: 1QNT) was prepared for docking. Screening of 1,842 FDA-approved compounds was performed using AutoDock Vina targeting the catalytic site around Cys145. Top hits were advanced to ADMET prediction and 100 ns MD simulations with GROMACS/CHARMM36. Stability was assessed via RMSD, RMSF, hydrogen bonds, and MM/PBSA free energies. Future experimental validation via ITC was proposed. Results: Rucaparib displayed the strongest predicted affinity (−11.3 kcal/mol), with Nilotinib (−10.8 kcal/mol) and Vorinostat (−10.5 kcal/mol) also outperforming TMZ (−5.8 kcal/mol). MD simulations confirmed stable protein-ligand complexes with persistent interactions at key residues (Cys145, Tyr114). All three maintained low RMSD values and formed multiple hydrogen bonds throughout the simulations, supporting binding stability under physiological conditions. MM/PBSA yielded highly favorable binding energies for Rucaparib (−64.3 kJ/mol). Compounds showed acceptable drug-likeness and predicted BBB permeability. Proposed ITC indicated strong binding for Rucaparib (Kd 0.42 μM). Conclusions: These three FDA-approved drugs represent promising MGMT inhibitor candidates that merit preclinical evaluation to overcome chemoresistance in glioblastoma.