Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

Elisabeth Rexen Ulven; Mette Trauelsen; Matjaz Brvar; Michael Lückmann; Line Ø Bielefeldt; Lisa K I Jensen; Thue W Schwartz; Thomas M. Frimurer

doi:10.1038/s41598-018-28263-7

Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

Elisabeth Rexen Ulven, Mette Trauelsen, Matjaz Brvar, Michael Lückmann, Line Ø Bielefeldt, Lisa K I Jensen, Thue W Schwartz, Thomas M. Frimurer

7 Citationer (Scopus)

62 Downloads (Pure)

Abstract

The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

Originalsprog	Engelsk
Artikelnummer	10010
Tidsskrift	Scientific Reports
Vol/bind	8
Udgave nummer	1
Sider (fra-til)	1-18
ISSN	2045-2322
DOI	https://doi.org/10.1038/s41598-018-28263-7
Status	Udgivet - 1 dec. 2018

Adgang til dokumentet

10.1038/s41598-018-28263-7

Structure-Activity Investigations and Optimisations of Nonmetabolite Agonists for the Succinate Receptor 1Forlagets udgivne version, 3,74 MB

Citationsformater

@article{88cbef969b2c43f79380581bffc56807,

title = "Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1",

abstract = "The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.",

author = "{Rexen Ulven}, Elisabeth and Mette Trauelsen and Matjaz Brvar and Michael L{\"u}ckmann and Bielefeldt, {Line {\O}} and Jensen, {Lisa K I} and Schwartz, {Thue W} and Frimurer, {Thomas M.}",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41598-018-28263-7",

language = "English",

volume = "8",

pages = "1--18",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "nature publishing group",

number = "1",

}

TY - JOUR

T1 - Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

AU - Rexen Ulven, Elisabeth

AU - Trauelsen, Mette

AU - Brvar, Matjaz

AU - Lückmann, Michael

AU - Bielefeldt, Line Ø

AU - Jensen, Lisa K I

AU - Schwartz, Thue W

AU - Frimurer, Thomas M.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

AB - The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

U2 - 10.1038/s41598-018-28263-7

DO - 10.1038/s41598-018-28263-7

M3 - Journal article

C2 - 29968758

SN - 2045-2322

VL - 8

SP - 1

EP - 18

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10010

ER -

Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater