Pharmacophore modeling, quantitative structure-activity relationship analysis, and in silico screening reveal potent glycogen synthase kinase-3β inhibitory activities for cimetidine, hydroxychloroquine, and gemifloxacin

The pharmacophoric space of glycogen synthase kinase-3 beta (GSK-3 beta) was explored using two diverse sets of inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophores and physicochemical descriptors that access self-consistent and predictive quantitative structure-activity relationship (QSAR) against 132 training compounds (r(123)(2) = 0.663 F = 24.6, r(LOO)(2) = 0.592, r(PRESS)(2) against 29 external test inhibitors = 0.695). Two orthogonal pharmacophores emerged in the QSAR, suggesting the existence of at least two distinct binding modes accessible to ligands within GSK-3 beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3 beta inhibitors retrieved from our in-house-built structural database of established drugs, namely, hydroxychloroquine, cimetidine, and gemifloxacin. Docking studies supported the binding modes suggested by the pharmacophore/QSAR analysis. In addition to being excellent leads for subsequent optimization, the anti-GSK-3 beta activities of these drugs should have significant clinical implications.