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.