Development of in silico models for pyrazoles and pyrimidine derivatives as cyclin-dependent kinase 2 inhibitors

CDK2 (cyclin-dependent kinase 2) is an attractive target for therapeutic intervention in cancer. In this work, quantitative structure–activity relationship (QSAR), molecular docking, and molecular dynamics (MD) studies were performed on three sets of 155 CDK2 inhibitors. The obtained models exhibit good predictive capability in both internal and external validations (q2 = 0.73, rpred2 = 0.94 for 6, 6-dimethyl pyrrolo [3,4-c]pyrazoles analogs, q2 = 0.62, rpred2 = 0.63 for imidazole pyrimidine amides analogs and q2 = 0.56, rpred2 = 0.58 for 4-(pyrazol-4-yl)-pyrimidines analogs). Furthermore, a comparison between 3D-contour map, docking and MD simulation explore in detail the binding modes and the key structural features impacting the interaction of each series of inhibitors with the CDK2 enzyme, which should be useful to aid the designing of new inhibitors with CDK2 improved biological response.

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• CDK2 is regarded as novel therapeutic targets for cancer chemotherapy.
• 3D-QSAR was performed on three different series of CDK2 inhibitors.
• H-bond properties are found to play crucial roles for the activity.
• The obtained results can help in the development of novel potent CDK2 inhibitors.