Acta Phys. -Chim. Sin. ›› 2009, Vol. 25 ›› Issue (05): 890-896.doi: 10.3866/PKU.WHXB20090409

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Molecular Docking and 3D-QSAR on Maleimide Derivatives as Glycogen Synthase Kinase-3β Inhibitors

WEI Zhuo, ZHANG Huai, CUI Wei, JI Ming-Juan   

  1. College of Chemistry and Chemical Engineering, Graduate University of the Chinese Academy of Sciences, Beijing 100049, P. R. China; Laboratory of Computational Geodynamics, Graduate University of the Chinese Academy of Sciences, Beijing 100049, P. R. China
  • Received:2008-10-20 Revised:2008-12-04 Published:2009-05-04
  • Contact: JI Ming-Juan


Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches were used to characterize the binding features of two different series of maleimide glycogen synthase kinase-3β(GSK-3β) inhibitors, 3-(indol-3-yl)-4-(1H-indazol-3-yl) maleimides and 3-(benzofuran-3-yl)-4-(indol-3-yl) maleimides. First, molecular docking was applied to characterize the binding modes and interactions between ligands and GSK-3β. A comparative molecular field analysis (CoMFA) and comparative molecular similarity indice analysis (CoMSIA) were then employed to develop 3D-QSAR models of 48 compounds. The excellent predictive capability of these 3D-QSAR models were validated by a satisfactory correlation coefficient using leave-one-out cross-validation q2 values (q2 values were 0.669 and 0.683 for CoMFA and CoMSIA, respectively). Satisfactory predictions on externally tested compounds also validated the models. Using the 3D-QSAR models, 9 molecules were designed with predicted good binding affinities in terms of molecular docking score and they also had good predicted values for inhibition.

Key words: GSK-3β, 3D-QSAR, CoMFA, CoMSIA, Molecular docking


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