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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. GSK3β 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-β-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one (βDGT), a natural xanthonoid present in many plant species, is reported to bind to the ATP-binding pocket of GSK3β 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 GSK3β 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 µM. The study envisages the use of βDGT as a natural ATP-competitive inhibitor of GSK3β and implicates its use in PCa patients on ADT, a cardiovascular disease risk, and other pathological conditions where GSK3 inhibition may be clinically important.HighlightsGSK3β is a multifaceted kinase known for its role in cancers, cardiovascular, and other diseases.In this study, βDGT, a xanthonoid, is reported to bind to the ATP-binding pocket of GSK3β.A comparison of βDGT binding with 5 known ATP-competitive inhibitors of GSK3β suggested the involvement of residues at the ATP binding site.The binding site analysis suggested an ATP-competitive mechanism of enzyme inhibition.Study envisages the use of βDGT as a natural ATP-competitive inhibitor of GSK3β and implicates its use in prostate cancer patients on androgen-deprivation therapy, a cardiovascular disease risk, and other pathological conditions. GSK3β is a multifaceted kinase known for its role in cancers, cardiovascular, and other diseases. In this study, βDGT, a xanthonoid, is reported to bind to the ATP-binding pocket of GSK3β. A comparison of βDGT binding with 5 known ATP-competitive inhibitors of GSK3β suggested the involvement of residues at the ATP binding site. The binding site analysis suggested an ATP-competitive mechanism of enzyme inhibition. Study envisages the use of βDGT as a natural ATP-competitive inhibitor of GSK3β and implicates its use in prostate cancer patients on androgen-deprivation therapy, a cardiovascular disease risk, and other pathological conditions. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

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