Identification of small molecule estrogen-related receptor α-specific antagonists and homology modeling to predict the molecular determinants as the basis for selectivity over ERRβ and ERRγ
| العنوان: | Identification of small molecule estrogen-related receptor α-specific antagonists and homology modeling to predict the molecular determinants as the basis for selectivity over ERRβ and ERRγ |
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| المؤلفون: | Susan P. Rohrer, Sheng Jian Cai, James Schaeffer, Elizabeth T. Birzin, J. Don Chen, Osvaldo A. Flores, Paul Zuck, Ralph T. Mosley, Michael J. Chisamore, Hilary A. Wilkinson, Gregory O'Donnell |
| المصدر: | Drug Development Research. 69:203-218 |
| بيانات النشر: | Wiley, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Estrogen-related receptor, Estrogen-related receptor alpha, Nuclear receptor, Biochemistry, Docking (molecular), Drug Discovery, Coactivator, Estrogen receptor, Homology modeling, Biology, Receptor |
| الوصف: | The estrogen-related receptor α (ERRα) was one of the first orphan receptors identified through a search for genes encoding proteins related to the steroid nuclear receptor, Estrogen Receptor α (ERα). The physiological role of ERRα has not yet been established nor has a natural ligand been elucidated. Importantly, research indicates that ERRα may be a novel drug target to treat breast cancer and/or metabolic disorders. A homogeneous time-resolved fluorescence (HTRF) assay has been developed to screen for ERRα-specific antagonists. This assay uses the ERR ligand binding domain and the coactivator interaction domain of Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) to examine the ability of compounds to antagonize the constitutive interaction between ERRα and the coactivator. A dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) was also created to counter screen compounds identified in the HTRF screen. Here we report the discovery of high-affinity ERRα subtype selective antagonists. Additionally, a homology model of ERRα in an antagonist conformation has been developed and after subsequent docking studies, we offer a model showing the molecular determinants that suggest why our novel tri-cyclic antagonist, N-[(2Z)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5 H dibenzo[a,d][7]annulen-5-amine, binds to ERRα with high affinity but does not bind to either ERRβ or ERRγ. Drug Dev Res 69:203–218, 2008. © 2008 Wiley-Liss, Inc. |
| تدمد: | 1098-2299 0272-4391 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::79f76f61b20d2f796a10f10b499f4ccfTest https://doi.org/10.1002/ddr.20246Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi...........79f76f61b20d2f796a10f10b499f4ccf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10982299 02724391 |
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