Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions
| Autor: | Kristoffer L. Egerod, Anne-Sofie Graae, Thue W. Schwartz, Birgitte Holst, Rie Nygaard, Thomas M. Frimurer, Franziska Mende, Lars-Ole Gerlach, Jakob Bondo Hansen, Maja S. Engelstoft |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Somatostatin secretion Chemistry Drug discovery Allosteric regulation Combinatorial chemistry 03 medical and health sciences 030104 developmental biology Biochemistry Drug Discovery Molecular Medicine Structure–activity relationship Homology modeling Binding site Receptor G protein-coupled receptor |
| Zdroj: | Journal of Medicinal Chemistry. 60:886-898 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b00648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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