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-3beta inhibitors.
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 3beta (GSK-3beta) 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-3beta inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3beta 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-3beta. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.
Kim
Ki Hwan
KH
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60612, USA. pkhkim@gmail.com
Gaisina
Irina
I
Gallier
Franck
F
Holzle
Denise
D
Blond
Sylvie Y
SY
Mesecar
Andrew
A
Kozikowski
Alan P
AP
D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D017706:Lisinopril / Q000737:chemistry / Q000494:pharmacology; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D008301:Maleimides; D017706:Lisinopril; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3