title: Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential cognition enhancers.
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.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Rima
authors.initials: R
authors.lastname: Hajjo
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003071:Cognition / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D023281:Genomics; D006801:Humans; D048088:Informatics / Q000379:methods*; D008024:Ligands; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D018697:Nootropic Agents; D011985:Receptors, Serotonin; D020845:Selective Estrogen Receptor Modulators; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D020849:Raloxifene Hydrochloride