Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine.
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.
Schapira
Matthieu
M
Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA. matthieu@molsoft.com
Abagyan
Ruben
R
Totrov
Maxim
M
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
D008024:Ligands; D020033:Protein Isoforms; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine; D000109:Acetylcholine