3D-QSAR STUDY OF MALEIMIDE ANALOGUES AS GLYCOGEN SYNTHASE KINASE-3 (GSK-3) INHIBITORS USING CoMSIA APPROACH

Several series of substituted maleimide derivatives (3-anilino-4-aryl, indolyl, oxaindolyl), and macrocyclic maleimides were reported as potent, selective GSK-3 inhibitors. In order to gain overall insight into structural prerequisites that influence biological activity, we adopted a ligand-based methodology - three-dimensional quantitative structure activity relationships which has been developed using the Field Based QSAR module from Schrodinger suite and a large collection of maleimide compounds (203). The CoMSIA model which was generated based on training set and validated on test set compounds (R-train(2)=0.833, Q(train)(2)=0.673, R-Pearson test=0.832) is reliable and can be used to predict novel inhibitors of GSK-3 belonging to the same structural class. The molecular structural features and field contour maps portrayed by 3D-QSAR model afforded relevant insights into the structure activity profile of maleimide derivatives. The CoMSIA model, confirm the experimental interaction pattern and is helpful for future lead compound optimization, design and prioritization of new inhibitors for chemical synthesis.