Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

AbstractGlycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensivein silicoand biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent within silicofindings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50=2.26 µM) vs. GSK-3β (IC50=4.23 µM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50=2.24 µM) than GSK-3α (IC50=5.14 µM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employingin vitroand preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.HighlightsCurrent GSK-3 inhibitors lack specificity and cause side effects.This study identifies potential GSK-3 isoform-specific natural compounds.Psoralidin is likely a better inhibitor for GSK-3α while Rosmarinic for GSK-3β.These natural compounds may be promising future treatments.