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.

1α, 25-二羟基维生素 D_3 是维生素 D_3 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。本研究旨在阐明负责与VDR和DBP结合的维生素D的构象。维生素D的构象分析表明，维生素D侧链移动的空间可分为四个不同的区域。我们设计了四种构象受限的类似物，其侧链仅限于占据四个空间区域之一。通过有机铜酸盐与烯酮的非对映选择性缀合加成作为关键步骤，立体选择性地合成了每种类似物。这些类似物的VDR和DBP亲和力表明了与VDR和DBP结合的重要区域在哪里。此外，四种类似物中的一种，其VDR亲和力比天然激素高近20倍，被发现具有最强的VDR亲和力。 VDR 结合亲和力尚未报道。基于这些发现，研究正在进展，以开发功能性配体，通过基因转录和新的选择性治疗药物来探测维生素 D 的作用。总之，利用计算机辅助构象分析、分子设计和化学合成，我们能够建议维生素 D 负责与 VDR 和 DBP 结合的基本三维结构，并鉴定出具有迄今为止已知的最高 VDR 亲和力的维生素 D 类似物。