Abstract
Cyclin-dependent kinases have essential role in the regulation of the cell division cycle. The structure-activity relationship of 4-cyclohexylmethoxypyrimidines, inhibitors of CDK2 as antitumor agents was explored. Since some of the studied 4-cyclohexylmethoxypyrimidines were reported to be among the most potent and selective CDK2 inhibitors reported to date, it was of interest to study QSAR. Useful QSAR equations were generated using dielectric energy (DE), N_Count, indicator parameter, Shadow_XYfrac and Jurs_RASA to consider quantitatively the effect of the structural variation of 4-cyclohexylmethoxypyrimidines on the inhibition of CDK2. The statistical measures such as r, r2, q2, and F values obtained for the training set were in acceptable range and hence this relationship was used and the equations were validated using a test set. The models obtained showed not only statistical significance but also predictive ability and highlights the active compounds spatial pose in the CDK2 inhibition and that minor values for DE combined with an NO substituent lead to an increasing of CDK2 inhibitory activity. The models obtained might be able to be used predictively to guide design of additional potential CDK2 inhibitors.
Keywords: CDK2 inhibitor, QSAR, Shadow_XYfrac, Jurs_RASA, DE, Antitumor agent, Cancer, Antitumor agents, Inhibitory activity, (CDKS), Kinase inhibitors (CKIs), Drug's biological activity, Monoheterocycles pyrimidine, Triazole, Pyrazole, Pyridine, Biheterocycles-purine, Forward-selection, Backward elimination methods, The dielectric energy (DE), Metabolic susceptibility, Leave-One Out (LOO-), Shadow, Xyfrace, Jurs-RASA
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