Targeting CDK1 and CDK2 in Cancer: From Cell-Cycle Biology to Selective Inhibitor Design, A Computational Perspective

Abstract

Cyclin-dependent kinases 1 and 2 (CDK1 and CDK2) are essential regulators of the eukaryotic cell cycle and compelling oncology drug targets. Their near-identical ATP-binding pockets, sharing a global backbone RMSD of ~0.72 Å, present a fundamental selectivity challenge: inhibitors must discriminate between two kinases whose active sites are virtually superimposable. This review bridges the biological rationale for CDK targeting with computational evidence from 100 ns all-atom molecular dynamics simulations, global conformational stability analysis, and alchemical free energy calculations for five CDK–inhibitor complexes involving Dinaciclib, AZD5438, and CGP74514A. Radius of gyration (Rg) analysis confirms that both kinases maintain native globular-fold stability throughout the simulation (Rg = 1.92–2.06 nm), indicating that differences in selectivity are not driven by global structural destabilization. van der Waals decoupling profiles from AZD5438 alchemical simulations reveal a characteristic non-monotonic free-energy landscape with a peak of ~8.7 kT in the early λvdW windows, providing direct energetic evidence for the steric and dispersive contributions to CDK2 selectivity.