Cyclin-dependent kinase-2 (CDK2) is a member of protein kinase family. It plays an important role in regulating various events of eukaryotic cell division cycle. Accumulated evidences indicated that over expression of CDK2 should cause the abnormal regulation of cell-cycle, which would be directly associated with hyperproliferation in cancer cells. Therefore, CDK2 was regarded as a potentially therapeutic target for cancer therapy. Knowledge of crystallography and availability of X-ray crystal structure of CDK2 have enabled us to understand the mode of CDK2 inhibition, which facilitated the development of numerous CDK2 inhibitors. Some of the CDK2 inhibitors were investigated clinically for their potential as anti-cancer agents. In this review, we present the structure, functions and activation of CDK2 by cyclin binding with special focus on recent advances in the development of different classes of CDK2 inhibitors. We also summarize different strategies to achieve subtype specificity either by targeting a binding pocket other than ATP, i.e. allosteric ligand binding site or by natural protein inhibitors capable to disrupt CDK2-cyclin complexes. It is possible to develop pharmacologically relevant cytotoxic agents by specifically inhibiting CDK2 activity with lesser toxicity than traditional chemotherapeutic agents.

CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the selectivity mechanism against CDK4 using a combined approach of 3D-QSAR, molecular docking, MESP, MD simulations, and binding free energy calculations. 3D-QSAR models were developed to propose structural determinants for CDK2 and CDK4 inhibition. High q² and r² values for CoMFA and CoMSIA models based on both internal and external validations suggested that the generated 3D-QSAR models may exhibit good capability to predict bioactivities of inhibitors against CDK2 or CDK4. Electrostatic potentials on the molecular surface have been discussed in detail for determining the binding affinity of studied inhibitors by combining molecular docking with MESP and Mulliken charge analyses. Binding free energy calculations suggested that the residues Gln85, Asp86, and Lys89 of CDK2 would play a critical role in selective CDK2 inhibition. The electrostatic interactions of an inhibitor with Glu144 and Asn145 of CDK4 may predominately drive CDK4 inhibition. These findings may provide a better structural understanding of the mechanism of CDK2 selective inhibition. The results obtained in the current study may provide valuable guidelines for developing novel potent and selective CDK2 inhibitors.

Cyclin dependent kinase 2 (CDK2) was regarded as a potentially therapeutic target for cancer therapy. Since the CDK family includes couples of high homology members, designing CDK2-selective inhibitors would provide valuable opportunities for the development of anticancer drugs with optimal efficacy. In this study, three thiazo-5-yl-pyrimidines as CDK2 inhibitors with different selectivity over cyclin dependent kinase 7 (CDK7) were examined to study the selectivity mechanism using a combined approach of computational techniques of flexible docking, EasyMIFs, molecular electrostatic potential (MESP), natural bond orbital (NBO), molecular dynamics (MD) simulations, and binding free energy calculations. Molecular simulations elicited new chemical insights into steric and electronic complementarities of these molecules to the binding sites of CDK2 and CDK7. The computed binding free energies were consistent with the ranking of their experimental binding affinities on CDK2 and CDK7. We also conducted in silico mutations of three key amino acids (CDK2: Gln85, Lys89, Asp145) to examine their impact on ligand binding with MD simulations and binding free energy calculations. The results indicated that these residues exhibited a strong tendency to mediate ligand–protein interactions through the H-bond and vdW interaction with CDK2-selective inhibitor. The present work may provide a better structural understanding of the molecular mechanism of CDK2 selective inhibition. The new computational insights presented in this study are expected to be valuable for the guidelines and development of new potent CDK2 inhibitors.