Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures.

Antoine Taly (1) , Claire Colas (2) , Thérèse Malliavin (2) , Arnaud Blondel (2) , Michael Nilges (2) , Pierre-Jean Corringer (3) , Delphine Joseph (4)

1 CAMB - Conception et application de molécules bioactives
2 Bioinformatique Structurale
3 Récepteurs-Canaux
4 Equipe de Synthèse Organique et Pharmacochimie de Composés d’Intérêt Biologique

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.

Keywords: Nicotinic acetylcholine receptor; Drug design; Virtual screening

Domains: Quantitative Methods [q-bio.QM]

Antoine Taly, Claire Colas, Thérèse Malliavin, Arnaud Blondel, Michael Nilges, et al.. Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures.. Journal of Molecular Graphics and Modelling, 2011, 30, pp.100-9. ⟨10.1016/j.jmgm.2011.06.008⟩. ⟨pasteur-01459822⟩