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

Abstract

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.

Highlights

• 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

Keywords:

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

Acknowledgements

IRM acknowledges Deshbandhu College, University of Delhi for the Study leave to pursue PhD at Jamia Hamdard (JH). SA acknowledges DBT, Ministry of Science and Technology, Govt. of India for the bioinformatics facility at JH under the Biotechnology Information System Network.

Author contributions

The study was conceived by SA and performed by IRM under the supervision of SA. RKBS helped in data analysis. The manuscript was written and finalized by SA and DL.

Disclosure statement

The authors declare no competing interests.