Comparative Structure-Based Molecular Docking Analysis of Clinically Approved CDK4/6 Inhibitors Targeting CDK6

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) are critical regulators of the G1–S phase transition of the cell cycle and represent major therapeutic targets in hormone receptor-positive breast cancer. Although several CDK4/6 inhibitors have been approved for clinical use, their comparative binding characteristics at the molecular level remain insufficiently understood. In this study, a structure-based molecular docking approach was employed to evaluate the binding affinities and interaction profiles of clinically approved and clinical-stage CDK4/6 inhibitors toward CDK6. The crystal structure of CDK6 in complex with palbociclib (PDB ID: 5L2I) was retrieved from the Protein Data Bank, and the docking protocol was validated by redocking the co-crystallized ligand. Molecular docking analyses of ribociclib, abemaciclib, trilaciclib, alvocidib, and dalpiciclib were carried out using AutoDock. The redocking procedure successfully reproduced the experimental binding mode with an RMSD value of 1.0 Å, confirming the reliability of the docking protocol. Among the investigated ligands, dalpiciclib exhibited the lowest binding energy (−11.68 kcal/mol), followed by trilaciclib (−11.09 kcal/mol), both showing stronger predicted binding affinity than the reference ligand palbociclib (−10.91 kcal/mol). Abemaciclib demonstrated comparable binding affinity, whereas ribociclib and alvocidib displayed relatively weaker binding energies. These findings indicate that dalpiciclib and trilaciclib may form more stable complexes with CDK6 compared to other clinically used inhibitors. This comparative in silico analysis provides structural insights into the binding behavior of clinical CDK4/6 inhibitors and may contribute to future optimization and development of CDK-targeted therapies.