3D QSAR for GSK-3beta inhibition by indirubin analogues.
Glycogen synthase kinase 3 (GSK-3) plays an important role in a diverse number of regulatory pathways by phosphorylation of several different cellular targets and its inhibitors have been evaluated as promising drug candidates. Indirubin analogues show favorable inhibitory activity targeting GSK-3beta, which is closely related to the property and position of substituents. Two methods were used to build 3D-QSAR models for indirubin derivatives. The conventional 3D-QSAR (ligand-based) studies were performed based on the lower energy conformations employing atom fit alignment rule. The receptor-based 3D-QSAR models were also derived using bioactive conformations obtained by docking the compounds to the active site of GSK-3. Conclusions of models based on two methods are similar and reliable. The results indicate that both ligand-based and receptor-based are feasible tools to build 3D-QSAR models. Contour maps of the receptor-based CoMSIA model (q(2) = 0.766, r(2) = 0.908, N (number of components) = 5) including the steric, electronic and hydrophobic fields were taken as representative to explain factors affecting activities of inhibitors.
Zhang
Na
N
Department of Chemistry, Zhejiang University, Hangzhou, China.
Jiang
Yongjun
Y
Zou
Jianwei
J
Zhang
Bing
B
Jin
Haixiao
H
Wang
Yanhua
Y
Yu
Qingsen
Q
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D007211:Indoles; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C027185:indirubin