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Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic dis...

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Autores principales: Diao, Yanyan, Jiang, Jing, Zhang, Shoude, Li, Shiliang, Shan, Lei, Huang, Jin, Zhang, Weidong, Li, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936786/
https://www.ncbi.nlm.nih.gov/pubmed/29761098
http://dx.doi.org/10.3389/fchem.2018.00140
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author Diao, Yanyan
Jiang, Jing
Zhang, Shoude
Li, Shiliang
Shan, Lei
Huang, Jin
Zhang, Weidong
Li, Honglin
author_facet Diao, Yanyan
Jiang, Jing
Zhang, Shoude
Li, Shiliang
Shan, Lei
Huang, Jin
Zhang, Weidong
Li, Honglin
author_sort Diao, Yanyan
collection PubMed
description Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC(50) values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC(50) = 6.47 μM), compounds 2a and 3a displayed 5- and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.
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spelling pubmed-59367862018-05-14 Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening Diao, Yanyan Jiang, Jing Zhang, Shoude Li, Shiliang Shan, Lei Huang, Jin Zhang, Weidong Li, Honglin Front Chem Chemistry Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC(50) values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC(50) = 6.47 μM), compounds 2a and 3a displayed 5- and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report. Frontiers Media S.A. 2018-04-30 /pmc/articles/PMC5936786/ /pubmed/29761098 http://dx.doi.org/10.3389/fchem.2018.00140 Text en Copyright © 2018 Diao, Jiang, Zhang, Li, Shan, Huang, Zhang and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Diao, Yanyan
Jiang, Jing
Zhang, Shoude
Li, Shiliang
Shan, Lei
Huang, Jin
Zhang, Weidong
Li, Honglin
Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title_full Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title_fullStr Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title_full_unstemmed Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title_short Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening
title_sort discovery of natural products as novel and potent fxr antagonists by virtual screening
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936786/
https://www.ncbi.nlm.nih.gov/pubmed/29761098
http://dx.doi.org/10.3389/fchem.2018.00140
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