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

Abstract

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 pyrazolo[4,3-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 pyrazolo[4,3-h]quinazoline core, the different substituents at three important points were replaced with diverse molecular fragments. The compounds resulting from fragments assembly with pyrazolo[4,3-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.

Keywords:

• 3D-QSAR
• cyclin-dependent kinase 2
• molecular fragment replacement
• Volsurf
• ADME

Acknowledgements

The work was financially supported by the Natural Science Foundation of Jiangsu Province, China (BK2009303), the National Natural Science Foundation of China (30973609), the National Major Science and Technology Project of China (Innovation and Development of New Drugs) (No. 2009ZX09501-003) and Qing Lan Project of Jiangsu Province, China.