De novo design of quinazoline derivatives as CDK2 inhibitors: 3D-QSAR,molecular fragment replacement and Volsurf predictions

Cyclin-dependent kinase 2 (CDK2) has appeared as an important drug target over the years with a multitude of therapeutic potentials. To design compounds with enhanced inhibitory potencies against CDK2, 3D-QSAR and molecular fragment replacement studies were performed on the pyrazolo4,3-h]quinazoline derivatives, a class of potent CDK2 inhibitors. The contours of 3D-QSAR model revealed important structural features of the inhibitors related to the active site of CDK2. Based on the pyrazolo4,3-h]quinazoline core, the different substituents at three important points were replaced with diverse molecular fragments. The compounds resulting from fragments assembly with pyrazolo4,3-h]quinazoline core were then scored with the robust 3D-QSAR model. Furthermore, the absorption, distribution, metabolism and excretion properties of these compounds were predicted by Volsurf to eliminate inappropriate compounds. Thirty-one new potential compounds were finally obtained. These results initiated us to further optimise and design new potential inhibitors.