Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

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Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. / Trauelsen, Mette; Rexen Ulven, Elisabeth; Hjorth, Siv A; Brvar, Matjaz; Monaco, Claudia; Frimurer, Thomas M; Schwartz, Thue W.

In: Molecular Metabolism, Vol. 6, No. 12, 12.2017, p. 1585-1596.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Trauelsen, M, Rexen Ulven, E, Hjorth, SA, Brvar, M, Monaco, C, Frimurer, TM & Schwartz, TW 2017, 'Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91', Molecular Metabolism, vol. 6, no. 12, pp. 1585-1596. https://doi.org/10.1016/j.molmet.2017.09.005

APA

Trauelsen, M., Rexen Ulven, E., Hjorth, S. A., Brvar, M., Monaco, C., Frimurer, T. M., & Schwartz, T. W. (2017). Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. Molecular Metabolism, 6(12), 1585-1596. https://doi.org/10.1016/j.molmet.2017.09.005

Vancouver

Trauelsen M, Rexen Ulven E, Hjorth SA, Brvar M, Monaco C, Frimurer TM et al. Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. Molecular Metabolism. 2017 Dec;6(12):1585-1596. https://doi.org/10.1016/j.molmet.2017.09.005

Author

Trauelsen, Mette ; Rexen Ulven, Elisabeth ; Hjorth, Siv A ; Brvar, Matjaz ; Monaco, Claudia ; Frimurer, Thomas M ; Schwartz, Thue W. / Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. In: Molecular Metabolism. 2017 ; Vol. 6, No. 12. pp. 1585-1596.

Bibtex

@article{10acc40b6b354078a4b43687d5020939,
title = "Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91",
abstract = "OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.CONCLUSIONS: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.",
keywords = "Journal Article",
author = "Mette Trauelsen and {Rexen Ulven}, Elisabeth and Hjorth, {Siv A} and Matjaz Brvar and Claudia Monaco and Frimurer, {Thomas M} and Schwartz, {Thue W}",
note = "Copyright {\circledC} 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.",
year = "2017",
month = "12",
doi = "10.1016/j.molmet.2017.09.005",
language = "English",
volume = "6",
pages = "1585--1596",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier",
number = "12",

}

RIS

TY - JOUR

T1 - Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

AU - Trauelsen, Mette

AU - Rexen Ulven, Elisabeth

AU - Hjorth, Siv A

AU - Brvar, Matjaz

AU - Monaco, Claudia

AU - Frimurer, Thomas M

AU - Schwartz, Thue W

N1 - Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.CONCLUSIONS: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.

AB - OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.CONCLUSIONS: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.

KW - Journal Article

U2 - 10.1016/j.molmet.2017.09.005

DO - 10.1016/j.molmet.2017.09.005

M3 - Journal article

VL - 6

SP - 1585

EP - 1596

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 12

ER -

ID: 189623577