Novel potent and selective bile acid derivatives as TGR5 agonists: Biological screening, structure-activity relationships, and molecular modeling studies
Novel potent and selective bile acid derivatives as TGR5 agonists: Biological screening, structure-activity relationships, and molecular modeling studies
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DOI：
10.1021/jm7015864
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Auwerx, Johan
中科院分区：
文献类型：
--
作者：
Sato, Hiroyuki;Macchiarulo, Antonio;Auwerx, Johan
TGR5是一种代谢型受体，它与G蛋白偶联，可诱导腺苷酸环化酶，已被确认为将胆汁酸与能量和葡萄糖内稳态控制相联系的分子纽带。为了揭示该受体的新型选择性调节剂，同时阐明TGR5激活的分子基础，我们在此报告了对一系列天然存在的胆汁酸、胆汁酸衍生物以及一些甾体激素进行的生物学筛选，这导致了新的强效且选择性的TGR5配体的发现。所测试化合物集合的生物学结果被用于扩展TGR5激动剂的构效关系，并建立一个TGR5活性的二元分类模型。该模型尤其能够揭示胆汁酸和甾体激素分子形状所共有的一些与TGR5激活相关的隐藏特性，因此可用于指导新型选择性强效TGR5激动剂的设计。
TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.