title: Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.
abstract: The G-protein-coupled receptor 39 (GPR39) is a G-protein-coupled receptor activated by Zn2+. We used a homology model-based approach to identify small-molecule pharmacological tool compounds for the receptor. The method focused on a putative binding site in GPR39 for synthetic ligands and knowledge of ligand binding to other receptors with similar binding pockets to select iterative series of minilibraries. These libraries were cherry-picked from all commercially available synthetic compounds. A total of only 520 compounds were tested in vitro, making this method broadly applicable for tool compound development. The compounds of the initial library were inactive when tested alone, but lead compounds were identified using Zn2+as an allosteric enhancer. Highly selective, highly potent Zn2+-independent GPR39 agonists were found in subsequent minilibraries. These agonists identified GPR39 as a novel regulator of gastric somatostatin secretion.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, University of Copenhagen , Blegdamsvej 3, DK-2200, Copenhagen, Denmark.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Franziska
authors.initials: F
authors.lastname: Mende
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Graae
authors.forename: Maja S
authors.initials: MS
authors.lastname: Engelstoft
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.forename: Rie
authors.initials: R
authors.lastname: Nygaard
authors.forename: Lars-Ole
authors.initials: LO
authors.lastname: Gerlach
authors.forename: Jakob Bondo
authors.initials: JB
authors.lastname: Hansen
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
mesh_terms: D000494:Allosteric Regulation; D055808:Drug Discovery; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*
chemical_list: C495797:GPR39 protein, human; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015032:Zinc