4.7 Article

Xanthone glucoside 2-β-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one binds to the ATP-binding pocket of glycogen synthase kinase 3β and inhibits its activity: implications in prostate cancer and associated cardiovascular disease risk

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JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 40, 期 17, 页码 7868-7884

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TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2021.1902857

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GSK3β kinase inhibitors; molecular docking; molecular dynamics simulation; luminescent kinase assay

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The study identifies a natural xanthonoid, beta DGT, as a potential ATP-competitive inhibitor of GSK3 beta that could be beneficial in reducing cardiovascular disease risk in prostate cancer patients undergoing ADT.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase which in the presence of ATP in its ATP-binding pocket transfers a phosphate to a primed substrate. GSK3 beta is an isoform of GSK3 which has been projected as a potent therapeutic target in human diseases including cancers and metabolic syndrome. Incidentally, cardiovascular disease is a common cause of non-cancer related deaths in prostate cancer (PCa) patients, mainly due to the effects of androgen-deprivation therapy (ADT), a mainstay for PCa treatment. Several small molecular inhibitors of GSK3 are either ATP-competitive (bind to the ATP-binding pocket), or non-ATP-competitive inhibitors (binding to the substrate-binding site of the enzyme). In this study, 2-beta-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one (beta DGT), a natural xanthonoid present in many plant species, is reported to bind to the ATP-binding pocket of GSK3 beta and inhibit its activity, as demonstrated by the molecular docking and molecular dynamics simulation analysis and experimental validation in vitro. A comparison of the binding affinities with five known ATP-competitive inhibitors of GSK3 beta suggested similarity in binding site residues in the ATP-binding pocket of the enzyme. The optimum inhibitory concentration of the xanthonoid as determined by the luminescent kinase assay was 200 mu M. The study envisages the use of beta DGT as a natural ATP-competitive inhibitor of GSK3 beta and implicates its use in PCa patients on ADT, a cardiovascular disease risk, and other pathological conditions where GSK3 inhibition may be clinically important.

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