Abstract
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-HT(6)R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT(6)R 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-HT(6)R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT(6)R 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / physiopathology
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Cell Line, Tumor
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Cloning, Molecular
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Cognition / drug effects*
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Drug Discovery / methods*
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Drug Evaluation, Preclinical
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Genomics
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Humans
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Informatics / methods*
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Ligands
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Nootropic Agents / chemistry
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Nootropic Agents / metabolism
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Nootropic Agents / pharmacology*
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Nootropic Agents / therapeutic use
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Quantitative Structure-Activity Relationship
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Raloxifene Hydrochloride / pharmacology
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Raloxifene Hydrochloride / therapeutic use
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Receptors, Serotonin / genetics
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Receptors, Serotonin / metabolism*
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Reproducibility of Results
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Selective Estrogen Receptor Modulators / chemistry
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Selective Estrogen Receptor Modulators / metabolism*
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Selective Estrogen Receptor Modulators / pharmacology*
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Selective Estrogen Receptor Modulators / therapeutic use
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Serotonin Antagonists / pharmacology
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Serotonin Antagonists / therapeutic use
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User-Computer Interface
Substances
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Ligands
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Nootropic Agents
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Receptors, Serotonin
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Selective Estrogen Receptor Modulators
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Serotonin Antagonists
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serotonin 6 receptor
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Raloxifene Hydrochloride