Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.
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Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions. / Frimurer, Thomas M.; Mende, Franziska; Graae, Anne-Sofie; Engelstoft, Maja S.; Egerod, Kristoffer L.; Nygaard, Rie; Gerlach, Lars-Ole; Hansen, Jakob Bondo; Schwartz, Thue W.; Holst, Birgitte.
In: Journal of Medicinal Chemistry, Vol. 60, No. 3, 2017, p. 886-898.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.
AU - Frimurer, Thomas M.
AU - Mende, Franziska
AU - Graae, Anne-Sofie
AU - Engelstoft, Maja S.
AU - Egerod, Kristoffer L.
AU - Nygaard, Rie
AU - Gerlach, Lars-Ole
AU - Hansen, Jakob Bondo
AU - Schwartz, Thue W.
AU - Holst, Birgitte.
PY - 2017
Y1 - 2017
N2 - The G-protein coupled receptor 39 (GPR39) is a G protein-coupled receptor activated by Zn2. We used a homol. model-based approach to identify small-mol. pharmacol. tool compds. 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 mini-libraries. These libraries were cherry-picked from all com. available synthetic compds. A total of only 520 compds. were tested in vitro, making this method broadly applicable for tool compd. development. The compds. of the initial library were inactive when tested alone, but lead compds. were identified using Zn2 as an allosteric enhancer. Highly selective, highly potent Zn2-independent GPR39 agonists were found in subsequent mini-libraries. These agonists identified GPR39 as a novel regulator of gastric somatostatin secretion. [on SciFinder(R)]
AB - The G-protein coupled receptor 39 (GPR39) is a G protein-coupled receptor activated by Zn2. We used a homol. model-based approach to identify small-mol. pharmacol. tool compds. 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 mini-libraries. These libraries were cherry-picked from all com. available synthetic compds. A total of only 520 compds. were tested in vitro, making this method broadly applicable for tool compd. development. The compds. of the initial library were inactive when tested alone, but lead compds. were identified using Zn2 as an allosteric enhancer. Highly selective, highly potent Zn2-independent GPR39 agonists were found in subsequent mini-libraries. These agonists identified GPR39 as a novel regulator of gastric somatostatin secretion. [on SciFinder(R)]
KW - pharmacophore screening GPR39 receptor gastric mucosa somatostatin secretion
U2 - 10.1021/acs.jmedchem.6b00648
DO - 10.1021/acs.jmedchem.6b00648
M3 - Journal article
C2 - 28045522
VL - 60
SP - 886
EP - 898
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -
ID: 174463411