Discovery of New Non‐Steroidal Farnesoid X Receptor Modulators Through 3D Shape Similarity Search and Structure‐Based Virtual Screening
Discovery of New Non‐Steroidal Farnesoid X Receptor Modulators Through 3D Shape Similarity Search and Structure‐Based Virtual Screening
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DOI：
10.1111/cbdd.12432
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发表时间：
2015-04
影响因子：
3
通讯作者：
Lei Wang;Pei Si;Yayun Sheng;Yingjie Chen;Ping Wan;Xu Shen;Yun Tang;Li-li Chen;Weihua Li
中科院分区：
文献类型：
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作者：
Lei Wang;Pei Si;Yayun Sheng;Yingjie Chen;Ping Wan;Xu Shen;Yun Tang;Li-li Chen;Weihua Li
法尼醇X受体（farnesoid X receptor，FXR）作为一种配体激活的转录因子，具有胆汁酸合成、脂质代谢、葡萄糖稳态等多种生物学功能，与多种疾病尤其是代谢综合征有关。在这项研究中，为了发现新的FXR调节剂，我们设计了一种结合3D形状相似性搜索和基于结构的对接方法的策略。以我们以前报道的两个FXR配体为参考分子，对Enamine数据库进行虚拟筛选，最终选择了59个化合物进行生物测定。其中，四个化合物在均相时间分辨荧光实验中显示出对FXR的激动或拮抗活性。在基于细胞的试验中发现其中两种是新的强效FXR拮抗剂，IC50值分别为8.39和6.53 μm。
As a ligand‐activated transcriptional factor, farnesoid X receptor (FXR) has a variety of biological functions, such as biosynthesis of bile acids, metabolism of lipid, and glucose homeostasis, and thus is related to multiple diseases, especially metabolic syndrome. In this study, to discover new FXR modulators, we have designed a strategy by combining 3D shape similarity search and structure‐based docking methods. Taking two FXR ligands that we previously reported as the reference molecules, virtual screening was performed against the Enamine database, and finally 59 compounds were selected for bioassay. Among them, four compounds exhibited agonistic or antagonistic activities against FXR in homogeneous time resolved fluorescence assay. Two of them were found to be new, potent FXR antagonists in cell‐based assay with IC50 values of 8.39 and 6.53 μm, respectively.