Conformational Analysis of Vitamin D Resposible for Binding to VDR and DBP

负责与 VDR 和 DBP 结合的维生素 D 的构象分析

基本信息

批准号：
07672418
负责人：
YAMAMOTO Keiko
金额：
$ 1.34万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

1alpha, 25-Dihydroxyvitamin D_3 is the homonally active form of vitamin D_3 taht regulates calcium metabolism, cell differentiation and immune systems, and exerts these functions by binding to the nuclear vitamin D receptor (VDR) and regulating the expression of target genes. This study was performed to clarify the conformation of vitamin D responsible for binding to VDR and DBP.Conformational analysis of vitamin D indicated that the space where vitamin D side chain moves about can be divided into four distinct regions. We designed four conformationally restricted analogs whose side chains are confined to occupy only one of four spatial regions. Each analog was synthesized stereoselectively via diastereoselective conjugate addition of organocuprate to enone as the key step. VDR and DBP affinities of these analogs indicated where is the important region to bind to VDR and DBP.Furthermore, one of the four analogs, whose VDR affinity was nearly 20 times as high as that of the native hormone, was found to have the strongest VDR binding affinity yet reported. On the basis of these findings, studies are progressing to develop functional ligands probing the vitamin D action through gene transcription and new selective therapeutic agents.In summary, using computer-aided conformational analysis, molecular design, and chemical synthesis, we were able to suggest the essential three-dimensional structure of vitamin D responsible for binding to VDR and DBP,and to identify an analog of vitamin D with the highest VDR affinity ever known.

1alpha，25-二羟基维生素D_3是维生素D_3 TAHT的同源活性形式，可调节钙代谢，细胞分化和免疫系统，并通过与核维生素D受体（VDR）结合并调节靶基因的表达来发挥这些功能。进行这项研究是为了阐明负责与VDR和DBP结合的维生素D的构象。维生素D的合法分析表明，维生素D侧链移动的空间可以分为四个不同的区域。我们设计了四个构型限制的类似物，它们的侧链仅限于占据四个空间区域之一。每个模拟都通过非对映选择性共轭添加有机液酸盐来立体选择，以作为关键步骤。这些类似物的VDR和DBP亲和力指示与VDR和DBP结合的重要区域是Furthermore，Furthermore是四个类似物之一，它们的VDR亲和力近20倍，是天然激素的高度高20倍VDR结合亲和力尚未报告。根据这些发现，研究正在进行开发功能配体，通过基因转录和新的选择性治疗剂探测维生素D作用。综上所述，使用计算机辅助构象分析，分子设计和化学合成，我们能够建议我们能够建议维生素D的基本三维结构负责与VDR和DBP结合，并鉴定有史以来最高VDR亲和力的维生素D的类似物。