In Silico Exploration Of The Interaction Mechanisms Of CDK2Inhibitors

Protein kinases (PKs) play very important roles in many pathways of human beings, and have become the second largest group of drug targets merely after G-protein-coupled receptors. The effects of one member of PKs, cyclin-dependent kinase (CDK) in the cell cycle are especially crucial. And CDK2, which interacts with cyclin A and cyclin E, draws much attention for its close correlation with oncology. Having been proved to be associated with many diseases for its vital role in cell cycle, CDK2is a promising target of anti-cancer drugs dealing with cell cycle disorders. In the present work, a total of111pyrazolo [1,5-a]pyrimidines (PHTPPs) as CDK2/cyclin A inhibitors were studied to conduct three-dimensional quantitative structure-activity analyses. The optimal comparative molecular similarity indices analysis model shows that Q2=0.516, RnCv2=0.912, Rpre2=0.914, Rm2=0.843, SEP=0.812, SEE=0.347with10components using steric, hydrophobic and H-bond donor field descriptors, indicating its effective internal and external predictive capacity. The contour maps further indicate that (1) bulky substituents in R1are beneficial while H-bond donor groups at this position are detrimental for the biological activities;(2) hydrophobic contributions in the R2area are favorable;(3) large and hydrophilic groups are well tolerated at the R3position (a close H-bond donor moiety is favorable while a distal H-bond donor moiety in this area is disfavored);(4) bulky and hydrophobic features in the R4region are beneficial and (5) the7-N-aryl substitution is crucial for the PHTPPs. Finally, docking and MD simulations demonstrate that PHTPP derivatives bind to CDK2being stabilized in a "flying bat" conformation mainly through the H-bond and hydrophobic contacts. Comparative studies indicate that PHTPP derivatives fit well within the ATP binding cleft in CDK2, with the core heterocyclic ring overlapping significantly with the adenine group of ATP despite a small deflection. In comparison to numerous inhibitors binding to the ATP pocket, PHTPP analogues follow the binding fashion of purine inhibitors. It is anticipated that the binding mechanism and structural features of PHTPP inhibitors studied in the present work will benefit the discovery of more potent CDK2inhibitors, and the valid PHTPP inhibitors will soon emerge from the large number of screening programmes to enter in clinical studies.