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bioRxiv · 10.1101/2024.04.22.590490

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

Ahmad, F.·Gupta, A.·Marzook, H.·Woodgett, J. R.·Saleh, M. A.·Qaisar, R.
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Abstract

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3 or GSK-3{beta} 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 comprehensive in silico and 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-3 and GSK-3{beta}, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3 (IC50=2.26 {micro}M) vs. GSK-3{beta} (IC50=4.23 {micro}M) while Rosmarinic acid was found to be more potent against GSK-3{beta} (IC50=2.24 {micro}M) than GSK-3 (IC50=5.14 {micro}M). 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-3 and Rosmarinic for GSK-3{beta} isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers. HighlightsO_LICurrent GSK-3 inhibitors lack specificity and cause side effects. C_LIO_LIThis study identifies potential GSK-3 isoform-specific natural compounds. C_LIO_LIPsoralidin is likely a better inhibitor for GSK-3 while Rosmarinic for GSK-3{beta}. C_LIO_LIThese natural compounds may be promising future treatments. C_LI

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Ahmad, F., Gupta, A., Marzook, H., Woodgett, J. R., Saleh, M. A., Qaisar, R.. 2024-04-22. Natural compound screening predicts novel GSK-3 isoform-specific inhibitors. https://doi.org/10.1101/2024.04.22.590490

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