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

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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.