Butyl Pocket Formation in the Vitamin D Receptor Strongly Affects the Agonistic or Antagonistic Behavior of Ligands

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• 作者：Nobuko Yoshimoto ; Yuta Sakamaki ; Minoru Haeta ; Akira Kato ; Yuka Inaba ; Toshimasa Itoh ; Makoto Nakabayashi ; Nobutoshi Ito ; Keiko Yamamoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4373-4381
• 全文大小：430K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Previously, we reported that 22S-butyl-25,26,27-trinor-1伪,24-dihydroxyvitamin D₃2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a鈥?b>c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a鈥?b>c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.