Integrated DFT, molecular docking, and molecular dynamics investigation of some novel 2-thiohydantoin analogues as potent CDK2 inhibitors for anticancer therapy

Abstract

Cancer progression is driven by dysregulation of cyclin-dependent kinase 2 (CDK2), a critical cell cycle regulator. This study employed an integrated computational approach combining Density Functional Theory (DFT), molecular docking, molecular dynamics (MD) simulations, and MM-PBSA calculations to evaluate 2-thiohydantoin derivatives as CDK2 inhibitors. DFT calculations revealed compounds 2b-e narrowest lowest unoccupied molecular orbital (LUMO)- highest occupied molecular orbital (HOMO) gaps (3.02-3.26 eV in DMSO) and highest electrophilicity indices (> 3.20 eV), indicating enhanced reactivity toward biological targets. QTAIM and Fukui function analyses identified key electrophilic centers (C2, O12, C14) and hydrogen bonding sites essential for protein interactions. Molecular docking against CDK2 (PDB: 1HCK) showed compounds 2c, 2d, and 2b exhibited superior binding affinities (-9.312, -9.303, and - 9.269 kcal/mol) compared to ATP (-8.460 kcal/mol), forming critical hydrogen bonds with Lys33 and Thr14. The 10 ns MD simulations confirmed stable binding, with compound 2f maintaining highest conformational stability (RMSD ~ 0.05 nm) and robust hydrogen bonding (mean: 2.70 bonds). MM-PBSA analysis revealed compound 2d achieved optimal binding affinity (ΔG_bind = -34.50 ± 0.42 kcal/mol) through balanced van der Waals interactions (-50.74 kcal/mol) and minimal desolvation penalty (52.40 kcal/mol). Compounds 2b, 2c, 2d, and 2f emerged as lead candidates for experimental validation as next-generation CDK2-targeted anticancer agents.