Docking of 3-amino-1H-indazoles complexed with glycogen synthase kinase 3 beta (GSK3β) was performed to gain insight into the structural requirements and preferred conformations of these inhibitors. The study was conducted on a selected set of 57 compounds with variation in structure and activity. We found that the most active compounds established three hydrogen bonds with the residues of the hinge region of GSK3β, but some of the less active compounds have other binding modes. In addition, models able to predict GSK3β inhibitory activities (IC(50) ) of the studied compounds were obtained by 3D-QSAR methods CoMFA and CoMSIA. Ligand-based and receptor-guided alignment methods were utilized. Adequate R(2) and Q(2) values were obtained by each method, although some striking differences existed between the obtained contour maps. Each of the predictive models exhibited a similar ability to predict the activity of a test set. The application of docking and quantitative structure-activity relationship together allowed conclusions to be drawn for the choice of suitable GSK3β inhibitors.
© 2011 John Wiley & Sons A/S.