3D QSAR for GSK-3β 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-3β, 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 (q² = 0.766, r² = 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.