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Efficient discovery of selective small molecule agonists of estrogen-related receptor gamma using combinatorial approach.

Authors
  • Kim, Yongju
  • Koh, Minseob
  • Kim, Don-Kyu
  • Choi, Hueng-Sik
  • Park, Seung Bum
Type
Published Article
Journal
Journal of Combinatorial Chemistry
Publisher
American Chemical Society
Publication Date
Jan 01, 2009
Volume
11
Issue
5
Pages
928–937
Identifiers
DOI: 10.1021/cc900081j
PMID: 19746993
Source
Medline
License
Unknown

Abstract

With the goal of discovering a selective agonist of estrogen-related receptor gamma (ERRgamma) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRgamma agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRgamma. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRgamma LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRgamma transcriptional activity with selectivity over ERRalpha/beta enables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERRgamma agonist, E6, with excellent selectivity over ERRalpha/beta.

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