Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of molecular modeling, 2009-12, Vol.15 (12), p.1463-1479

Ort / Verlag

Berlin/Heidelberg: Springer-Verlag

Erscheinungsjahr

2009

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 pIC 50 values has the following statistics: R 2 (cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R 2  = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R 2  = 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.