Discovery of Potent CDK2 Inhibitors Through Structure-Based Virtual Screening and MD Simulation Studies.

Abstract

Cyclin-dependent kinase 2 (CDK2) is a crucial regulator of the cell cycle and a promising target for cancer treatment. In this study, five known inhibitors were used to create a receptor-based pharmacophore model that includes an aromatic ring, hydrogen bond donors and acceptors, a negatively charged group, and a hydrophobic region. This model screened the Asinex database and found 1881 hits. Molecular docking narrowed the selection to the 10 best candidates (MD1-MD10), with MD1-MD5 showing strong binding affinities, with docking scores between -11.66 and -10.56 kcal/mol. These five compounds were further tested using ADME/T profiling, DFT calculations, and 100 ns molecular dynamics simulations. Principal component analysis (PCA) and free energy landscape (FEL) evaluations further confirmed stable conformational behavior across the MD simulation trajectories. The HOMO-LUMO gaps suggested stable electronic properties, and the MD simulations confirmed complex stability, with RMSD and RMSF values ranging from 2.0 to 2.8 Å. Overall, MD1-MD5 demonstrated excellent binding, structural stability, and pharmacokinetic properties, making them strong candidates for future CDK2-targeted anticancer research.