3D-QSAR and Molecular Docking Studies on 3-anilino-4-arylmaleimide Derivatives as Glycogen Synthase Kinase-3β Inhibitors

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer’s disease. It is important to inhibit GSK-3 selectively and the net effect of the GSK-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR) studies on novel class of 3-anilino-4-aryl maleimide derivatives to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for alignment of the molecules. Statistically significant CoMSIA (r²(cv) = 0.614, r²(ncv) = 0.948) and CoMFA (r²(cv) = 0.652, r² (ncv) = 0.958) models were generated using 57 molecules in training set. The predictive ability of CoMSIA and CoMFA models was determined using a test set of 17 molecules which gave predictive correlation coefficients (r² (pred) ) of 0.87 and 0.82, respectively, indicating good predictive power. Based upon the information derived from CoMSIA and CoMFA contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new anilino aryl maleimide derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems; hence suggesting that newly designed molecules can be more potent and selective towards GSK-3β inhibition. © 2011 John Wiley & Sons A/S.