Computer-Aided Molecular Design Of CDK4 Inhibitors

Cyclin-dependent-kinases 4 (CDK4) is a Ser/Thr protein kinase, playing an important role in cell cyclin . The CDK4 consists of regulatory and catalytic subunits.Losing control of cyclin is relevant to lack of CKI which is related to cancer.As the drug of anti-cancer,CKIS attract more and more people's attention.The thesis is about cyclin-dependent-kinases 4 (CDK4), inhibitors of pyrimidine- pyrazolyl analogues and the enolic tautomer . Homology modeling method,molecular docking and three dimensional structure-activity relationship (3D-QSAR) had been applied. There are four main parts, as follows:In the first part, using cyclin-dependent-kinases 2 (CDK2) as a structural template , the 3D structure of CDK4 was built with homology modeling method. Rational analysis of the modeled structure was performed. Subsequently, fifty-seven known inhibitors of pyrimidine- pyrazolyl analogues were selected for docking study. The result shows that there exists a good correlation between the calculated binding energy and the inhibitory activity with the correlation coefficient (R) being 0.571. While, different docking patterns had been researched, some rational explanations were provided for the different activities of these inhibitors.In the second part, using comparative molecular field analysis(CoMFA) and comparative similarity indices analysis(CoMSIA),three dimensional structure-activity relationship (3D-QSAR) have been studied on inhibitors of CDK4,based on the structures getting from docking . The resulting CoMFA and CoMSIA models have cross-validated correlation coefficient q~2 of 0.545 and 0.478 ,and non-crossvalidated correlation coefficient r~2 of 0.974 and 0.934 respectively,which show great predictive ability on both test set and training set . The 3D-QSAR contour maps of CoMFA and CoMSIA provide smooth and interpretable explanation of the structure-activity relationship for the compounds,which will guide the furtherresearch...From the structures of pyrimidine- pyrazolyl analogues (keto), enolic tautomershave some proportion in the enantiotropic reaction of keto- enolic . We should consider the influence of the enolic tautomers in the drug design. So for the further studies,we saw about the interaction of CDK4 and enolic tautomer. Inhibitory activity of the inhibitors of pyrimidine- pyrazolyl analogues is determined by keto and enolic tautomer.So three dimensional structure-activity relationship (3D-QSAR) should be studied on inhibitors of enolic tautomer.In the third part, fifty-seven known inhibitors' enolic tautomer were selected for docking study. The result shows that there exists a good correlation between the calculated binding energy and the inhibitory activity with the correlation coefficient (R) being 0.601. While, different docking patterns had been researched, some rational explanations were provided for the different activities of these inhibitors.In the last part, using comparative molecular field analysis(CoMFA) and comparative similarity indices analysis(CoMSIA),three dimensional structure-activity relationship (3D-QSAR) have been studied on inhibitors of enolic tautomer,based on the structures getting from docking. The resulting CoMFA and CoMSIA models have cross-validated correlation coefficient q~2 of 0.492 and 0.626 ,and non-crossvalidated correlation coefficient r~2 of 0.887 and 0.978 respectively,which show great predictive ability on both test set and training set . The 3D-QSAR contour maps of CoMFA and CoMSIA provide smooth and interpretable explanation of the structure-activity relationship for the compounds,which will guide the further research..