3D-QSAR and 3D-QSSR studies of thieno[2,3-d] pyrimidin-4-yl hydrazone analogues as CDK4 inhibitors by CoMFA analysis

Aim： To investigate the structural basis underlying potency and selectivity of a series of novel analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones as cyclin-dependent kinase 4 （CDK4） inhibitors and to use this information for drug design strategies. Methods： Three-dimensional quantitative structure-activity relationship （3D-QSAR） and three-dimensional quantitative structure-selectivity relationship （3D-QSSR） models using comparative molecular field analysis （CoMFA） were conducted on a training set of 48 compounds. Partial least squares （PLS） analysis was employed. External validation was performed with a test set of 9 compounds. Results： The obtained 3D-QSAR model （q2=0.724, r2=0.965, r2pred=0.945） and 3D-QSSR model （q2=0.742, r2=0.923, r2pred=0.863） were robust and predictive. Contour maps with good compatibility to active binding sites provided insight into the potentially important structural features required to enhance activity and selectivity. The contour maps indicated that bulky groups at R1 position could potentially enhance CDK4 inhibitory activity, whereas bulky groups at R3 position have the opposite effect. Appropriate incorporation of bulky electropositive groups at R4 position is favorable and could improve both potency and selectivity to CDK4. Conclusion： These two models provide useful information to guide drug design strategies aimed at obtaining potent and selective CDK4 inhibitors.