1. Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures
- Author
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Arnaud Blondel, Antoine Taly, Michael Nilges, Thérèse E. Malliavin, Delphine Joseph, Pierre-Jean Corringer, Claire Colas, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Récepteurs-Canaux, Equipe de Synthèse Organique et Pharmacochimie de Composés d’Intérêt Biologique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), and Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Models, Molecular ,Pyridines ,Amino Acid Motifs ,Nicotinic Antagonists ,Neonicotinoids ,MESH: Amino Acid Motifs ,Acetylcholine binding ,0302 clinical medicine ,Materials Chemistry ,MESH: Animals ,Nicotinic Agonists ,Spectroscopy ,Lymnaea ,0303 health sciences ,Chemistry ,Imidazoles ,MESH: Lobeline ,Nitro Compounds ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Computer Graphics and Computer-Aided Design ,MESH: Nitro Compounds ,Nicotinic acetylcholine receptor ,Nicotinic agonist ,MESH: Imidazoles ,MESH: Models, Molecular ,Protein Binding ,Virtual screening ,Surface Properties ,Stereochemistry ,Aconitine ,MESH: Carrier Proteins ,Benzylidene Compounds ,Drug design ,03 medical and health sciences ,MESH: Computer Simulation ,MESH: Lymnaea ,MESH: Nicotinic Agonists ,Animals ,MESH: Protein Binding ,Computer Simulation ,MESH: Aconitine ,Physical and Theoretical Chemistry ,Binding site ,030304 developmental biology ,Acetylcholine receptor ,MESH: Surface Properties ,Binding Sites ,MESH: Pyridines ,MESH: Nicotinic Antagonists ,Bridged Bicyclo Compounds, Heterocyclic ,MESH: Binding Sites ,Docking (molecular) ,Lobeline ,Cholinergic ,MESH: Bridged Bicyclo Compounds, Heterocyclic ,MESH: Benzylidene Compounds ,Carrier Proteins ,030217 neurology & neurosurgery - Abstract
International audience; 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.
- Published
- 2011
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