Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity
Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity
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DOI：
10.1016/j.bmc.2015.10.026
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发表时间：
2015-11-15
影响因子：
3.5
通讯作者：
Yamamoto, Keiko
中科院分区：
文献类型：
--
作者：
Anami, Yasuaki;Sakamaki, Yuta;Yamamoto, Keiko
1 α，25-二羟基维生素D3通过与维生素D受体（VDR）结合发挥作用。我们正在继续研究22-烷基取代配体对VDR口袋结构的改变及其与激动/拮抗活性之间的关系。化合物2（22-H）、3（22 S-Et）和4（22 S-Bu）分别为VDR激动剂、部分激动剂和拮抗剂。在这里，我们描述了22 S-己基类似物5（22 S-Hex）的合成和生物学评价，其被设计为比4更强的VDR拮抗剂。出乎意料的是，当与VDR结合时，5显示部分激动活性而非拮抗活性，表明侧链越大，拮抗活性将越强不一定是真的。X-射线晶体学分析的VDR-配体结合域（VDR-LBD）容纳化合物5表明，部分激动剂活性的5是依赖于混合人口的激动和拮抗构象。由于VDR-LBD的大的构象变化，化合物5的结合可能不会使复合物进入唯一的拮抗构象。从该研究中发现，通过配体的22-烷基链长度可以微调VDR的激动/拮抗活性。(C)2015作者由爱思唯尔有限公司出版。这是一篇开放获取的文章，使用CC BY许可证（http：//creativecommons.org/licenses/by/4.0/）。
1 alpha,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compounds 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, respectively. Here, we describe the synthesis and biological evaluation of 22S-hexyl analog 5 (22S-Hex), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallographic analysis of the VDR-ligand-binding domain (VDR-LBD) accommodating compound 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compound 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study it was found that fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).