title: Understanding channel blocking in the nicotinic acetylcholine receptor.
abstract: Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.
authors.affiliation: Instituto de Investigaciones Bioquímicas (CONICET), CC 857, 8000 Bahía Blanca, Argentina. mortells@mail.retina.ar
authors.forename: M O
authors.initials: MO
authors.lastname: Ortells
authors.forename: G E
authors.initials: GE
authors.lastname: Barrantes
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002714:Chlorisondamine / Q000378:metabolism / Q000494:pharmacology; D004996:Ethidium / Q000378:metabolism / Q000494:pharmacology; D018738:Hexamethonium / Q000378:metabolism / Q000494:pharmacology; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009861:Onium Compounds / Q000378:metabolism / Q000494:pharmacology; D010393:Pempidine / Q000378:metabolism / Q000494:pharmacology; D011335:Proadifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011796:Quinacrine / Q000378:metabolism / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014320:Triphenylmethyl Compounds / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018733:Nicotinic Antagonists; D009861:Onium Compounds; D011978:Receptors, Nicotinic; D014320:Triphenylmethyl Compounds; C011561:triphenylmethylphosphonium; C006072:QX-222; D018738:Hexamethonium; C019001:meproadifen; D008012:Lidocaine; D011335:Proadifen; D004996:Ethidium; D011796:Quinacrine; D002714:Chlorisondamine; D010393:Pempidine; D000109:Acetylcholine