12th International Conference of Pharmaceutical Sciences

Glycogen synthase kinase 3-beta (GSK-3β) represents a significant therapeutic target associated with Alzheimer’s disease1 and its inhibition by allosteric modulators have shown to be advantageous due to less chance of side-effects.2 In this work, we performed Structure-Activity Relationships studies with a set of forty reported2 allosteric GSK-3β modulators by constructing Principal Component Analysis (PCA) models, using their binary biological activities and calculated molecular descriptors. 2D-3D molecular descriptors were calculated using TSAR, MarvinSketch, and, also, considering our previous docking studies, which afforded consistent binding poses and corresponding 3D features concerning the binding modes of the inhibitors towards GSK-3β. The best PCA model split active from inactive compounds according to their structural similarity depicted by Dipole Moment, Shape Flexibility Index, VAMPionizationpotential and Accessible Solvent Area. Such descriptors provide coherent information on interactions that can occur between compounds and the allosteric GSK-3β cavity. This PCA model may support virtual screening campaigns to pursue novel candidates to act as allosteric GSK-3β modulators.