title: 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.affiliation: Center for Drug Discovery Technologies, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Gil Nam
authors.initials: GN
authors.lastname: Lee
authors.forename: Chi Hyun
authors.initials: CH
authors.lastname: Kim
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Ikyon
authors.initials: I
authors.lastname: Kim
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
mesh_terms: D001667:Binding, Competitive; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3