Pharmacophore Modeling, Quantitative Structure–Activity Relationship Analysis, and in Silico Screening Reveal Potent Glycogen Synthase Kinase-3β Inhibitory Activities for Cimetidine, Hydroxychloroquine, and Gemifloxacin

Abstract

The pharmacophoric space of glycogen synthase kinase-3beta (GSK-3beta) 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 (2) 123 = 0.663, F = 24.6, r (2) LOO = 0.592, r (2) PRESS 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-3beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3beta 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-3beta activities of these drugs should have significant clinical implications.

Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequentin vitro/in vivoevaluation

“…In spite of a centuries long history of folk medical use, large quantities in the food supply and many studies attempting to pin down its effects at the molecular level, the field is still uncertain as to how the apparently multiple targets of curcumin cooperate or synergize to exert its effects. Furthermore, the fact that many GSK-3b inhibitors have arisen as promising drugs for several diseases such as diabetes type II, cancer, Alzheimer disease and chronic inflammatory disease [29][30][31][32][33] encouraged us to evaluate possible inhibitory effect for curcumin on GSK-3b.…”

“…The in vitro activity was expressed as the concentration of curcumin that inhibited GSK-3b activity by 50% (IC 50 ) using tau protein as substrate [32,33,41]. Unsurprisingly, curcumin illustrated potent inhibitory action against GSK-3b with an IC 50 value of 66.3 nM.…”

“…Plasmodial GSK is highly homologous to human GSK-3b [34] while human GSK-3b is involved in many signaling pathways. Inhibition of GSK-3b was recently suggested as a new molecular mechanism for hydroxychloroquine [33], a well known anti-malarial and anti-inflammatory drug. Interestingly, the reported hypoglycemic effects of hydroxychloroquine [49] can be also explained by its potent inhibitory action of GSK.…”

“…This mixture was incubated over 1 h at room temperature. The detection of Tau phosphorylation was performed as follows [32,33,41]: The GSK-3b reaction mixtures were diluted 1:1 with sodium azide aqueous solution (15 mM) to achieve a final Tau protein concentration of 250 pg/mL. Then 100 mL aliquots of this solution were pipetted into the wells of the Tau [pS396] phosphoELISA kit (Biosource, USA).…”

In-Silico Approach Towards Protein Targets Related to Diabetes Mellitus-An Overview

“…The compounds which show inhibition activity against Glycogen synthase kinase-3â have been used as drug candidates for the treatment of many diseases such as type II diabetes, cancer, Alzheimer's disease, mood disorders, bipolar disorders, stroke, and chronic inûammatory [19][20][21][22][23] . Currently there are small molecules used as Glycogen synthase kinase-3b inhibitors in clinical studies for the treatment of diabetes mellitus 24 .…”