文献类型：期刊文献

英文题名：Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

作者：Diao, Yanyan[1];Jiang, Jing[1];Zhang, Shoude[1];Li, Shiliang[1];Shan, Lei[2];Huang, Jin[1];Zhang, Weidong[2];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Sch Pharm, Shanghai, Peoples R China;[2]Second Mil Med Univ, Sch Pharm, Dept Phytochem, Shanghai, Peoples R China

年份：2018

卷号：6

外文期刊名：FRONTIERS IN CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000431124400001)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501 and the Fundamental Research Funds for the Central Universities. SL is also sponsored by Shanghai Sailing Program (No. 18YF1405100).

语种：英文

外文关键词：FXR; antagonist; virtual screening; molecular docking; similarity searching; natural product

摘要：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 IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3 a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 mu M, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 mu M), 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, themolecular basis of these antagonists against FXR was also elucidated in this report.