title: Virtual screening of CB(2) receptor agonists from bayesian network and high-throughput docking: structural insights into agonist-modulated GPCR features.
abstract: The relevance of CB(2)-mediated therapeutics is well established in the treatment of pain, neurodegenerative and gastrointestinal tract disorders. Recent works such as the crystallization of class-A G-protein-coupled receptors in a range of active states and the identification of specific anchoring sites for CB(2) agonists challenged us to design a reliable agonist-bound homology model of CB(2) receptor. Docking-scoring enrichment tests of a high-throughput virtual screening of 140 compounds led to 13 hits within the micromolar affinity range. Most of these hits behaved as CB(2) agonists, among which two novel full agonists emerged. Although the main challenge was a high-throughput docking run targeting an agonist-bound state of a CB(2) model, a prior 2D ligand-based Bayesian network was computed to enrich the input commercial library for 3D screening. The exclusive discovery of agonists illustrates the reliability of this agonist-bound state model for the identification of polar and aromatic amino acids as new agonist-modulated CB(2) features to be integrated in the wide activation pathway of G-protein-coupled receptors.
authors.affiliation: Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques, Université Lille-Nord de France, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renault
authors.forename: Xavier
authors.initials: X
authors.lastname: Laurent
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.forename: Jamal
authors.initials: J
authors.lastname: El Bakali
authors.forename: Roxane
authors.initials: R
authors.lastname: Mansouri
authors.forename: Philippe
authors.initials: P
authors.lastname: Gervois
authors.forename: Régis
authors.initials: R
authors.lastname: Millet
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Christophe
authors.initials: C
authors.lastname: Furman
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
mesh_terms: D001499:Bayes Theorem; D001665:Binding Sites; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D008024:Ligands; D043885:Receptor, Cannabinoid, CB2