Drug Design for mutant Vitamin D receptor

维生素D受体（VDR）属于类固醇/甲状腺激素核受体超家族。2000年Moras等测定了维生素D受体与1α，25-二羟维生素D_3的配体结合结构域（LBD）的X射线晶体结构，揭示了配体与LBD-VDR的结合方式。25（OH）_2D_3]。我们发现A环修饰的类似物2α-（3-羟丙基）-和2α-（3-羟丙氧基）-1，25（OH）_2D_3（O1C_3和O2C_3）能比天然激素更好地与突变体VDR（R274 A）结合，该突变体与HVDRR突变体R274 L相似，失去了与1α，25（OH）_2D_3的1α-羟基的氢键。我们还研究了对接模型。

Vitamin D receptor (VDR) belongs to the steroid/thyroid hormone nuclear receptor superfamily. The X-ray crystal structure of the ligand binding domain (LBD) of VDR with 1α,25-dihydroxyvitamin D_3 was determined by Moras et al. in 2000 and the binding mode between ligands and LBD-VDR was revealed.Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1α,25-dihydroxyvitamin D_3 [1α,25(OH)_2D_3]. We found that the A ring-modified analogues, 2α-(3-hydroxypropyl)-and 2α-(3-hydroxypropoxy)-1α,25(OH)_2D_3, (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1α-hydroxyl group of 1α,25(OH)_2D_3. We have also studied on docking models.