Abstract:

Objective To screen out novel allosteric small-molecule CDK2 inhibitors in verified allosteric pocket based on the crystal structure of CDK2 (PDB ID: 3PXF). Methods Virtual screening was performed via computer-aided drug design according to the allosteric site in CDK2 protein crystal. The interaction modes between the compounds and CDK2 were comprehensively analyzed. The CDK2 in vitro kinase activity detection system was established and the in vitro bioactivity of the compounds was primarily studied. Results Top 1000 compounds were obtained by virtual screening and 10 of them were selected and purchased. Compounds S2 and S5 showed favorable inhibitory effect and their inhibitory rates against CDK2 at the concentration of 100 μmol/L were 57.59% and 41.64%, respectively. Conclusion By utilization of virtual screening, structural analysis, and biological activity test, two lead compounds S2 and S5 were screened out, which can significantly inhibit the activity of CDK2. This work lays a foundation for design and development of novel allosteric small-molecule CDK2 inhibitors.

Key words: CDK2, cell cycle, virtual screening, allosteric inhibitor