title: Ligand selectivity for the acetylcholine binding site of the rat alpha4beta2 and alpha3beta4 nicotinic subtypes investigated by molecular docking.
abstract: The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.
authors.affiliation: Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Paul Scherrer Institute, Rämistrasse 100,CH-8091 Zürich, Switzerland.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Gerrit
authors.initials: G
authors.lastname: Westera
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: P A
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D000109:Acetylcholine / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001384:Azetidines / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000737:chemistry; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D012908:Snails; D013237:Stereoisomerism; D013816:Thermodynamics; D014981:Xenopus
chemical_list: C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; C104288:A 85380; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; D008024:Ligands; D009419:Nerve Tissue Proteins; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; C082748:epibatidine; D000109:Acetylcholine