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

1α，25-二羟基维生素D3是维生素D3taht的同源活性形式，通过与维生素D核受体(VDR)结合，调节靶基因表达，调节钙代谢、细胞分化和免疫系统。本研究旨在阐明维生素D与VDR和DBP结合的构象。对维生素D的构象分析表明，维生素D侧链的运动空间可分为四个不同的区域。我们设计了四个构象受限的类似物，它们的侧链被限制在四个空间区域中的一个区域。以有机铜与烯酮的非对映选择性共轭加成反应为关键步骤，立体选择性地合成了每一个类似物。这些类似物的VDR和DBP亲和力指示了VDR和DBP结合的重要区域在哪里。此外，四个类似物中的一个被发现具有最强的VDR结合亲和力，其VDR亲和力几乎是天然激素的20倍。在这些发现的基础上，开发通过基因转录和新的选择性治疗药物来探索维生素D作用的功能配体的研究正在取得进展。综上所述，利用计算机辅助构象分析、分子设计和化学合成，我们能够提出负责与VDR和DBP结合的维生素D的基本三维结构，并鉴定出迄今已知的具有最高VDR亲和力的维生素D类似物。

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.