Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl) maleimides as GSK-3β inhibitors

Ki Hwan Kim, Irina Gaisina, Franck Gallier, Denise Holzle, Sylvie Y. Blond, Andrew Mesecar, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3β (GSK-3β) inhibitors. The approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3β inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3β are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC50 values has the following statistics: R2(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R2 = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R2 = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3β. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.

Original languageEnglish (US)
Pages (from-to)1463-1479
Number of pages17
JournalJournal of Molecular Modeling
Volume15
Issue number12
DOIs
StatePublished - 2009

Keywords

  • 3D-QSAR
  • Benzofuran-3-yl-(indol-3-yl)maleimides
  • Binding mode
  • CoMFA
  • CoMSIA
  • Docking
  • GSK-3beta inhibitors
  • X-ray

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

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