Investigation of Novel Cyclin‐Dependent Kinase 4 Inhibitors for Cancer Treatment: In Silico Approach Using Natural Product Libraries

Abstract Cancer remains a leading cause of mortality, often characterized by uncontrolled cell proliferation often driven by dysregulated cell cycle progression regulated by cyclin‐dependent kinases (CDKs). CDK4, a key regulator of the G1‐to‐S phase transition, is frequently overexpressed in various cancers. Inhibiting Cyclin Dependent Kinase 4 (CDK4) selectively offers a promising therapeutic strategy to induce cell cycle arrest. This study employed structure‐based pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics ‐ Poisson Boltzmann Surface area (MM‐PBSA) analysis to identify novel CDK4 inhibitors from natural product libraries. Two lead compounds, CAP03464597 and UKR1436403, displayed exceptional binding affinity and selectivity. Detailed interaction analyses revealed strong hydrogen bonding stabilizing ligand binding within the active site and hydrophobic interactions further reinforced ligand affinity. MD simulations confirmed the conformational stability of ligand‐bound complexes, with minimal fluctuations and sustained interactions throughout 300 ns simulations. Free energy decomposition pinpointed hotspot residues contributing significantly to binding affinity. These findings underscore the potential of computer‐aided drug discovery in identifying selective CDK4 inhibitors and highlight natural products as a valuable source for anticancer therapeutics. Furthermore, the promising in silico results suggest that CAP03464597 and UKR1436403 warrant further experimental validation, including biochemical assays and cellular studies, to establish their efficacy as potential CDK4‐targeted anticancer agents.