title: Relating protein pharmacology by ligand chemistry.
abstract: The identification of protein function based on biological information is an area of intense research. Here we consider a complementary technique that quantitatively groups and relates proteins based on the chemical similarity of their ligands. We began with 65,000 ligands annotated into sets for hundreds of drug targets. The similarity score between each set was calculated using ligand topology. A statistical model was developed to rank the significance of the resulting similarity scores, which are expressed as a minimum spanning tree to map the sets together. Although these maps are connected solely by chemical similarity, biologically sensible clusters nevertheless emerged. Links among unexpected targets also emerged, among them that methadone, emetine and loperamide (Imodium) may antagonize muscarinic M3, alpha2 adrenergic and neurokinin NK2 receptors, respectively. These predictions were subsequently confirmed experimentally. Relating receptors by ligand chemistry organizes biology to reveal unexpected relationships that may be assayed using the ligands themselves.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th St, San Francisco California 94143-2550, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keiser
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Blaine N
authors.initials: BN
authors.lastname: Armbruster
authors.forename: Paul
authors.initials: P
authors.lastname: Ernsberger
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D001665:Binding Sites; D030562:Databases, Protein; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D008024:Ligands; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry*; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins