Novel GSK-3β inhibitors from sequential virtual screening
Novel GSK-3β inhibitors from sequential virtual screening
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DOI：
10.1016/j.bmc.2007.10.047
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发表时间：
2008-01-15
影响因子：
3.5
通讯作者：
Pae, Ae Nim
中科院分区：
文献类型：
--
作者：
Kim, Hye-Jung;Choo, Hyunah;Pae, Ae Nim
Glycogen synthase kinase-3 (GSK-3 beta) 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-3 beta inhibitors. The final 56 hit compounds were carefully selected considering predicted docking mode in crystal structures. Subsequent enzyme assay for human GSK-3 beta 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-3 beta crystal structure. (c) 2007 Elsevier Ltd. All rights reserved.
