Open AccessDiscovery of a Novel Class of ERRα Agonists
Author(s) -
Tsuyoshi Shinozuka,
Shuichiro Ito,
Takako Kimura,
Masanori Izumi,
Kenji Wakabayashi
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00100
Subject(s) - coactivator , computational biology , ligand (biochemistry) , chemistry , virtual screening , drug discovery , receptor , bioinformatics , stereochemistry , combinatorial chemistry , biochemistry , biology , gene , transcription factor
A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure-activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate 5c and the key interaction between the protein and ligand. Since both analogues avoided PPARγ transcriptional activity, they can be useful tool compounds for investigating biological ERRα functions.