Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening.
Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening.
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DOI：
10.3389/fchem.2018.00140
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发表时间：
2018
影响因子：
5.5
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Diao Y;Jiang J;Zhang S;Li S;Shan L;Huang J;Zhang W;Li H
法尼醇X受体（FXR）是核受体家族的一员，通过调节特定靶基因参与多种生理过程。 FXR 作为转录调节因子的关键作用使其成为多种疾病的有前景的靶标，尤其是与糖尿病和胆汁淤积等代谢性疾病相关的疾病。然而，由于缺乏适当的 FXR 调制器，FXR 的基本激活机制仍然不清楚。为了识别潜在的 FXR 调节剂，通过基于结构的虚拟筛选策略和随后的基于命中的相似性搜索方法筛选了包含 4,000 多种化合物的内部天然产物数据库 (NPD)。经过酵母双杂交 (Y2H) 测定后，六种天然产物被鉴定为 FXR 拮抗剂，可阻断 CDCA 诱导的 SRC-1 关联。化合物2a（一种带有多环骨架的二萜）和3a（具有链支架的芫酮）的IC50值分别低至1.29和1.79 μM。与对照化合物古古甾酮 (IC50 = 6.47 μM) 相比，化合物 2a 和 3a 对 FXR 的拮抗活性分别高出 5 倍和 3 倍。值得注意的是，这两种代表性化合物与其他报道的 FXR 拮抗剂的拓扑相似性较低。根据假定的结合姿势，本报告还阐明了这些 FXR 拮抗剂的分子基础。
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 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 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.