13 ビタミンDレセプターのリガンド認識、有機化学的アプローチ(口頭発表の部)

抄録

Conformational analysis of the side chain of 1α,25-dihydroxyvitamin D_3 [1,25-(OH)_2D_3, 1] and its 20-epimer 2 revealed that the spatial region occupied by the side chain of these vitamin Ds can be divided to four areas. We designed and synthesized four diastereomers 3-6 at C(20) and C(22) of 22-methyl-1,25-(OH)_2D_3 whose side-chain mobility is restricted in one of these four areas. We tested biological activities of these four analogs. These studies allowed us to propose the relationship between the spatial region of the vitamin D side-chain and the activity, an active space group concept. This concept has been generally accepted as explaining the three-dimensional structure and activity relationship of almost all known vitamin D analogs. We constructed the three-dimensional structure of the ligand binding domain (LBD) of vitamin D receptor (VDR) based on the crystal structure of retinoic acid receptor by the homology modeling technique. We docked 1,25-(OH)_2D_3 1 as a ligand into the constructed VDR-LBD. Three residues forming the hydrogen bonds with the functionally important 1α- and 25-hydroxyl groups of 1 were identified and confirmed by the mutational analysis: the 1α-hydroxyl group is forming pincer type hydrogen bonds with S237 and R274 and the 25-hydroxyl group is interacting with H397. By the computational docking studies based on the mutational analysis of the VDR, we obtained the docking models of the VDR with the functionally and structurally interesting ligands. From these studies we suggested key structural factors to bestow the augmented activities on 20-epi-vitamin Ds.