title: Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures.
abstract: Numerous high-resolution crystallographic structures of the acetylcholine binding protein (AChBP), a molluscan cholinergic protein, homologous to the extracellular domain of nicotinic acetylcholine receptors, are available. This offers opportunities to model the interaction between various ligands and the acetylcholine binding site. Herein we present a study of the interplay between ligand binding and motions of the C-loop capping the binding site. Nicotinic agonists and antagonists were docked on AChBP X-ray structures. It is shown that the studied agonists and antagonists can be discriminated according to their higher affinities for structures respectively obtained in the presence of agonists or antagonists, highlighting the fact that AChBP structures retain a pharmacological footprint of the compound used in crystallography experiments. A detailed analysis of the binding site cavities suggests that this property is mainly related to the shape of the cavities.
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, 74 Route du Rhin-BP 60024, 67401 Illkirch Cedex, France. a.taly@unistra.fr
authors.forename: Antoine
authors.initials: A
authors.lastname: Taly
authors.forename: Claire
authors.initials: C
authors.lastname: Colas
authors.forename: Thérèse
authors.initials: T
authors.lastname: Malliavin
authors.forename: Arnaud
authors.initials: A
authors.lastname: Blondel
authors.forename: Michael
authors.initials: M
authors.lastname: Nilges
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Corringer
authors.forename: Delphine
authors.initials: D
authors.lastname: Joseph
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000737:chemistry; D020816:Amino Acid Motifs; D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry*; D003198:Computer Simulation; D007093:Imidazoles / Q000737:chemistry; D008120:Lobeline / Q000737:chemistry; D008195:Lymnaea; D008958:Models, Molecular; D000073943:Neonicotinoids; D018722:Nicotinic Agonists / Q000737:chemistry*; D018733:Nicotinic Antagonists / Q000737:chemistry*; D009574:Nitro Compounds / Q000737:chemistry; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D013499:Surface Properties
chemical_list: C428944:AChBP protein, Lymnaea; D001597:Benzylidene Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D007093:Imidazoles; D000073943:Neonicotinoids; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009574:Nitro Compounds; D011725:Pyridines; C054634:methyllycaconitine; C082359:imidacloprid; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D008120:Lobeline; C082748:epibatidine; D000157:Aconitine