期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 12, 页码 5704-5719出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm2011657
关键词
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资金
- NIH research grant [GM066940]
- NIH contract
- Michael Hooker Chair in Protein Therapeutics and Translational Proteomics
- University of Jordan scholarship
- Tripos
- Chemical Computing Group
- eduSoft
- [RO1MH61887]
- [U19MH82441]
We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure-Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5-HT6R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT6R actives. Second, we queried chemogenomics data from the Connectivity Map (http://www.broad.mit.edu/cmap/) with the gene expression profile signatures of Alzheimer's disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT6R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT6R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations.
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