title: Novel GSK-3beta inhibitors from sequential virtual screening.
abstract: Glycogen synthase kinase-3 (GSK-3beta) has been emerging as a key therapeutic target for type-2 diabetics, Alzheimer's disease, cancer, and chronic inflammation. For the purpose of finding biologically active and novel compounds and providing new idea for drug-design, we performed virtual screening using commercially available database. Three-dimensional common feature pharmacophore model was developed by using HipHop program provided in Catalyst software and it was used as a query for screening database. Recursive partitioning (RP) model was developed as a filtering system, which was able to classify active and inactive compounds. Eventually, a sequential virtual screening procedure (SQSP) was conducted by applying the common feature pharmacophore and RP model in succession to discover novel potent GSK-3beta inhibitors. The final 56 hit compounds were carefully selected considering predicted docking mode in crystal structures. Subsequent enzyme assay for human GSK-3beta protein confirmed that three compounds of these hit compounds exhibit micromolar inhibitory activity. Here, we report novel hit compounds and their binding mode in the active site of GSK-3beta crystal structure.
authors.affiliation: Life Science Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3