Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.

Thomas M. Frimurer; Franziska Mende; Anne-Sofie Graae; Maja S. Engelstoft; Kristoffer L. Egerod; Rie Nygaard; Lars-Ole Gerlach; Jakob Bondo Hansen; Thue W. Schwartz; Birgitte. Holst

doi:10.1021/acs.jmedchem.6b00648

Model-Based Discovery of Synthetic Agonists for the Zn²⁺-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.

Thomas M. Frimurer, Franziska Mende, Anne-Sofie Graae, Maja S. Engelstoft, Kristoffer L. Egerod, Rie Nygaard, Lars-Ole Gerlach, Jakob Bondo Hansen, Thue W. Schwartz, Birgitte. Holst

Novo Nordisk Foundation Center for Protein Research

15 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	3
Pages (from-to)	886-898
Number of pages	13
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00648
Publication status	Published - 9 Feb 2017

Keywords

pharmacophore screening GPR39 receptor gastric mucosa somatostatin secretion

Access to Document

10.1021/acs.jmedchem.6b00648

Cite this

Frimurer, T. M., Mende, F., Graae, A-S., Engelstoft, M. S., Egerod, K. L., Nygaard, R., Gerlach, L-O., Hansen, J. B., Schwartz, T. W., & Holst, B. (2017). Model-Based Discovery of Synthetic Agonists for the Zn²⁺-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions. Journal of Medicinal Chemistry, 60(3), 886-898. https://doi.org/10.1021/acs.jmedchem.6b00648

Frimurer, TM, Mende, F, Graae, A-S, Engelstoft, MS, Egerod, KL, Nygaard, R, Gerlach, L-O, Hansen, JB, Schwartz, TW & Holst, B 2017, 'Model-Based Discovery of Synthetic Agonists for the Zn²⁺-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.', Journal of Medicinal Chemistry, vol. 60, no. 3, pp. 886-898. https://doi.org/10.1021/acs.jmedchem.6b00648

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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.",

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