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.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Renault N,Laurent X,Farce A,El Bakali J,Mansouri R,Gervois P,Millet R,Desreumaux P,Furman C,Chavatte Pdoi
10.1111/cbdd.12095subject
Has Abstractpub_date
2013-04-01 00:00:00pages
442-54issue
4eissn
1747-0277issn
1747-0285journal_volume
81pub_type
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