title: Discovery of α7-nicotinic receptor ligands by virtual screening of the chemical universe database GDB-13.
abstract: The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBD(MQN)) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at  www.gdb.unibe.ch . This virtual screening procedure selected 31 504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in  Xenopus  oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery.
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Blum
authors.forename: Ruud
authors.initials: R
authors.lastname: van Deursen
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Milena
authors.initials: M
authors.lastname: Mayer
authors.forename: Justus J
authors.initials: JJ
authors.lastname: Bürgi
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D000818:Animals; D016208:Databases, Factual; D055808:Drug Discovery; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D020409:Molecular Motor Proteins; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D008024:Ligands; D020409:Molecular Motor Proteins; D011978:Receptors, Nicotinic; D054852:Small Molecule Libraries; D064569:alpha7 Nicotinic Acetylcholine Receptor