Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects

Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form...

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Autores principales: Jin, Yifeng, Han, Younho, Khadka, Daulat Bikram, Zhao, Chao, Lee, Kwang Youl, Cho, Won-Jea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5046141/
https://www.ncbi.nlm.nih.gov/pubmed/27695006
http://dx.doi.org/10.1038/srep34661
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author Jin, Yifeng
Han, Younho
Khadka, Daulat Bikram
Zhao, Chao
Lee, Kwang Youl
Cho, Won-Jea
author_facet Jin, Yifeng
Han, Younho
Khadka, Daulat Bikram
Zhao, Chao
Lee, Kwang Youl
Cho, Won-Jea
author_sort Jin, Yifeng
collection PubMed
description Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.
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spelling pubmed-50461412016-10-11 Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects Jin, Yifeng Han, Younho Khadka, Daulat Bikram Zhao, Chao Lee, Kwang Youl Cho, Won-Jea Sci Rep Article Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662. Nature Publishing Group 2016-10-03 /pmc/articles/PMC5046141/ /pubmed/27695006 http://dx.doi.org/10.1038/srep34661 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Jin, Yifeng
Han, Younho
Khadka, Daulat Bikram
Zhao, Chao
Lee, Kwang Youl
Cho, Won-Jea
Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title_full Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title_fullStr Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title_full_unstemmed Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title_short Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects
title_sort discovery of isoquinolinoquinazolinones as a novel class of potent pparγ antagonists with anti-adipogenic effects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5046141/
https://www.ncbi.nlm.nih.gov/pubmed/27695006
http://dx.doi.org/10.1038/srep34661
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