Efficient Discovery of Selective Small Molecule Agonists of Estrogen-Related Receptor gamma using Combinatorial Approach
- Authors
- 김용주
- Issue Date
- 9월-2009
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF COMBINATORIAL CHEMISTRY, v.11, no.5, pp.928 - 937
- Indexed
- SCOPUS
- Journal Title
- JOURNAL OF COMBINATORIAL CHEMISTRY
- Volume
- 11
- Number
- 5
- Start Page
- 928
- End Page
- 937
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/140056
- DOI
- 10.1021/cc900081j
- ISSN
- 1520-4766
- Abstract
- With the goal of discovering a selective agonist of estrogen-related receptor gamma (ERR gamma) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERR gamma agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERR gamma. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies oil the receptor cavities of ERR gamma LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERR gamma transcriptional activity with selectivity over ERR alpha/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 ERR gamma agonist, E6, with excellent selectivity over ERR alpha/beta.
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