Structure-Activity Relationship And Molecular Design Studies On Purine Derivatives As CDK2 Inhibitors Based On Computer Simulation Technology

Cyclin-dependent kinase 2?CDK2?is one of the most promising and attractive target for treating cancer.To date,most of the CDK2 inhibitors reported have poor efficacy on cancer and toxic and side effects on normal cells.Therefore,it is pressing to design and develop novel potent CDK2 inhibitors.In this paper,to design novel potent CDK2 inhibitors,molecules modeling studies were performed on recently reported 35 purine class CDK2 inhibitors by combining three-dimensional quantitative structure-activity relationship?3D-QSAR?,virtual screening,molecular docking and molecular dynamics simulation methods.Comparative molecular field analysis?CoMFA?and comparative molecular similarity indices analysis?CoMSIA?models were constructed based on three different alignment methods.Besides,all possible combinations of CoMSIA field were considered during the construction of CoMSIA models,separately.The optimal CoMFA model(q²=0.743,r²_pred=0.991),CoMSIA model(q²=0.808,r²_pred=0.99)along with Topomer CoMFA model(q²=0.779,r²_pred=0.962) exhibit good internal and external predictive capabilities.QSAR models reveal that proper bulky R₁substituent;bulky positively charged hydrophilic substituent having hydrogen bond donor properties near–NH₂ at R₂ position;introducing hydrophobic substituent near the benzene ring of R₂;avoiding bulky and negatively charged substituent at R₃ position are favorable for activity.R-groups optimizing activity were obtained by virtual screening,novel compounds were designed using these R-groups.The QSAR models predictions and docking results demonstrated that 35 novel compounds designed have good predictive activity and binding affinity.Molecular docking and dynamics simulations results indicated that Glu81,Leu83,Asp86,Lys89,Lys33 and Gln131 are important residues which can form significant hydrogen bonds with ligand,respectively.The findings and resulted newly designed 35 compounds of this paper could provide valuable guidance for the development,further design and structural optimization of novel and effective CDK2 inhibitors.