Identification of small molecules that inhibit GSK-3beta through virtual screening.

Abstract

Glycogen synthase kinase-3beta (GSK-3beta) is involved in glycogen metabolism, neuronal cell development, osteoblast differentiation. Small molecule inhibitors of GSK-3beta have various therapeutic potential for the treatment of diabetes type II, bipolar disorders, stroke and chronic inflammatory disease. To identify GSK-3beta inhibitors with novel scaffold from chemical library, we primarily screened out putative inhibitors through computer modeling and subsequently evaluated the inhibitory activity of selected compounds against GSK-3beta by in vitro Z'-LYTEtrade mark assay. A series of compound KRMs strongly inhibited phosphorylation of its substrate with IC(50) value of approximately 0.5microM. Also, we demonstrated that KRM-189 and KRM-191 competed with ATP for GSK-3beta, leading to decreased Vmax and constant Km with increasing concentrations of ATP as determined from Lineweaver-Berk equation. Moreover, they showed the selectivity for GSK-3beta over other kinases with IC(50) values of 2 to 10microM or more Incubation of cells with KRM-191 with highly selective and potent inhibitory activity caused accumulation of beta-catenin, downstream of GSK-3beta signaling pathway, indicating that small molecule can prevent degradation of beta-catenin via GSK-3beta inhibition. Our results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors.

• Authors: Nam Sook Kang, Gil Nam Lee, Chi Hyun Kim, Myung Ae Bae, Ikyon Kim, Young Sik Cho
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 2 Pg. 533-7 (Jan 15 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19081248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• Binding, Competitive
• Computer Simulation
• Enzyme Inhibitors (metabolism, pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Phosphorylation
• Signal Transduction