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Virtual Screening of CB2 Receptor Agonists from Bayesian Network and High-Throughput Docking: Structural Insights into Agonist-Modulated GPCR Features

Authors

  • Nicolas Renault,

    1. 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
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  • Xavier Laurent,

    1. 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
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  • Amaury Farce,

    Corresponding author
    1. 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
    2. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
      Corresponding author: Amaury Farce, amaury.farce-2@univ-lille2.fr
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  • Jamal El Bakali,

    1. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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  • Roxane Mansouri,

    1. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, Plate-forme de binding et biologie moléculaire, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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  • Philippe Gervois,

    1. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, Plate-forme de binding et biologie moléculaire, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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  • Régis Millet,

    1. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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  • Pierre Desreumaux,

    1. Université Lille-Nord de France, Faculté de Médecine, Amphis J et K, INSERM U995, Boulevard du Professeur Jules Leclerc, 59045 Lille Cedex, France
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  • Christophe Furman,

    1. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, Plate-forme de binding et biologie moléculaire, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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  • Philippe Chavatte

    1. 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
    2. Institut de Chimie Pharmaceutique Albert Lespagnol, Université Lille-Nord de France, EA 4481, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France
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Corresponding author: Amaury Farce, amaury.farce-2@univ-lille2.fr

Abstract

The relevance of CB2-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 CB2 agonists challenged us to design a reliable agonist-bound homology model of CB2 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 CB2 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 CB2 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 CB2 features to be integrated in the wide activation pathway of G-protein-coupled receptors.

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