Acta Phys. -Chim. Sin. ›› 2009, Vol. 25 ›› Issue (04): 645-654.doi: 10.3866/PKU.WHXB20090402

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3D-QSAR and Molecular Docking Study on Selectivity of Indolocarbazole Series as Cyclin-Dependent Kinase Inhibitors

 SUN Ni-Yue, LU Tao, CHEN Ya-Dong, HAO Lan-Hu, XU Yan, LI Rui-Jun   

  1. Basic Science School, China Pharmaceutical University, Nanjing 210009, P. R. China
  • Received:2008-10-14 Revised:2008-12-31 Published:2009-03-31
  • Contact: CHEN Ya-Dong


Cyclin-dependent kinases (CDKs) have appeared as important anti-tumor targets over the years. Given that large numbers of kinases share conserved ATP binding pockets, the identification of a particular CDK inhibitor is currently under active investigation. This study was concerned with the design of CDK inhibitors with enhanced inhibitory potencies and subtype specificity. Specifically, CDK2-QSAR(quantitative structure-activity relationship) and CDK4-QSSR(quantitative structure-selectivity relationship) CoMFA(comparative molecular field analysis) studies were carried out on indolocarbazole derivatives as CDK inhibitors. The developed models have a cross validated correlation co-efficient q2 of 0.722 and 0.703 and a non-cross validated correlation co-efficient r2 of 0.977 and 0.946, respectively, which thus show a great predictive capability. These models suggested that side chain substituents of R5 and R6 of indolocarbazoles are expected to improve the selectivity of the molecules. CoMFA contour maps and the presumed binding modes provide an interpretable explanation of selectivity and this will guide further research.

Key words: Cyclin-dependent kinase, Indolocarbazole derivatives, 3D-QSAR, 3D-QSSR, CoMFA, Molecular docking