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VOL. 10, ISSUE 2 (2026)
Targeting CDK1 and CDK2 in cancer: From cell-cycle biology to selective inhibitor design, a computational perspective
Authors
Ganga Grazielia Chrisna, Chen Qu
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. Integrated with the cell-cycle biology of CDK/cyclin
complexes and the pharmacological classification of kinase inhibitors (Types
I–IV), these findings establish a multi-scale framework, from oncogenic
signaling pathways to sub-Ångström pocket dynamics, for rational CDK2-selective
drug design.
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Pages:89-94
How to cite this article:
Ganga Grazielia Chrisna, Chen Qu "Targeting CDK1 and CDK2 in cancer: From cell-cycle biology to selective inhibitor design, a computational perspective". International Journal of Chemical Science, Vol 10, Issue 2, 2026, Pages 89-94
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