Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies

Glycogen synthase kinase-3 beta (GSK-3 beta) is a promising target for therapeutic invasion of Alzheimer's disease (AD). The kinase enzyme plays major role in pathological process for the formation of beta-amyloid plaques and neurofibrillary tangles in AD. In the present study, structure-based pharmacophore and ligand-based 3D QSAR, HQSAR and pharmacophore mapping studies have been emphasized to explore the possible structural requirement of this potential kinase inhibitors using a structurally diverse set of compounds. The developed models were validated with the interaction study at the catalytic cleft. The 3D QSAR studies yield robust models of CoMFA R-2 = 0.965, se = 0.212, Q(2) = 0.525, R-pred(2) = 0.709, r(m)(2) = 0.579 and CoMSIA: R-2 = 0.935, se = 0.289, Q(2) = 0.581, R-pred(2) = 0.723, r(m)(2) = 0.935, that explain the importance of steric, electrostatic, hydrogen bond (HB) acceptor of the molecule for inhibition of GSK-3 beta. The HQSAR study (R-2 = 0.871, se = 0.400, Q(2) = 0.639, R-pred(2) = 0.721, r(m)(2) = 0.664) indicated the fragments of the molecular fingerprints that might be important for inhibition. Both structure-and ligand-based pharmacophore mapping proposed that acceptor and donor features of the molecule are essential for receptor-ligand interactions. Molecular diversity provides an opportunity on wide range of applicability for the GSK-3 beta inhibitors, and depicts information on the structural and properties requirement for effective binding at the active site selectivity that minimize the side effects with therapeutic benefits.