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 language | English (US) |
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Pages (from-to) | 1463-1479 |
Number of pages | 17 |
Journal | Journal of Molecular Modeling |
Volume | 15 |
Issue number | 12 |
DOIs | |
State | Published - 2009 |
Externally published | Yes |
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
- Inorganic Chemistry
- Computational Theory and Mathematics