Novel GSK-3beta inhibitors from sequential virtual screening.

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Kim HJ, Choo H, Cho YS, No KT, Pae AN

Novel GSK-3beta inhibitors from sequential virtual screening.

Bioorg Med Chem. 2008 Jan 15;16(2):636-43. Epub 2007 Oct 22.

PubMed ID

18006321 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
SB-409513	Glycogen synthase kinase-3 beta	IC 50 (nM)	76	N/A	N/A	Details