Molecular dynamics simulations reveal the determinants of cyclin-dependent kinase 2 inhibition by 5-nitrosopyrimidine derivatives

Cyclin-dependent kinase 2 (CDK2) is a kinase involved in the regulation of cell cycle, being responsible for triggering DNA synthesis. Aberrant control of CDK activity, resulting in the loss of orderly cell cycle progression, has been directly associated with the molecular pathology of cancer. Hence, CDKs represent attractive targets for anticancer therapy. In recent years the class of nitrosopyrimidines has caught attention for the design of CDK inhibitors. Three compounds belonging to this class (4, 5 and 6) were considered herein: despite their structural correlation, their inhibitory potency varied across several log units. A well-tempered metadynamics (WT-METAD) simulation was used to explore the free energy surface (FES) for the three systems. The study has revealed that the most potent compound (4) can form a hydrogen bond with Asp86, in addition to the bonding scheme shared by this class of compounds. On the contrary, compound 6 is unable to assume the “productive” conformation due to an unfavourable electrostatic interaction of its amino group. Further dynamical characterization was carried out for the three systems through unbiased molecular dynamics and steered molecular dynamics. The biophysical insight obtained through state-of-the-art simulations enabled a deeper understanding of the structure-activity relationships of nitrosopyrimidine CDK2 inhibitors and gave new hints for the design of new molecules belonging to this class.