title: Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine.
abstract: BACKGROUND
  Nicotine is a psychoactive drug presenting a diverse array of biological activities, some positive, such as enhancement of cognitive performances, others negative, such as addiction liability. Ligands that discriminate between the different isotypes of nicotinic acetylcholine receptors (nAChRs) could present improved pharmacology and toxicity profile.
  
  
  RESULTS
  Based on the recent crystal structure of a soluble acetylcholine binding protein from snails, we have built atomic models of acetylcholine and nicotine bound to the pocket of four different human nAChR subtypes. The structures of the docked ligands correlate with available biochemical data, and reveal that the determinants for isotype selectivity are relying essentially on four residues, providing diversity of the ligand binding pocket both in terms of Van der Waals boundary, and electrostatic potential. We used our models to screen in silico a large compound database and identify a new ligand candidate that could display subtype selectivity.
  
  
  CONCLUSIONS
  The nAChR-agonist models should be useful for the design of nAChR agonists with diverse specificity profiles.
authors.affiliation: Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA. matthieu@molsoft.com
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
mesh_terms: D000109:Acetylcholine / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009538:Nicotine / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine; D000109:Acetylcholine