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。Moras等（2000）测定了VDR与1α，25-二羟基维生素D_3的配体结合域（LBD）的x射线晶体结构，揭示了配体与LBD-VDR的结合模式。遗传性维生素D抗性佝偻病（HVDRR）是一种由维生素D受体突变引起的遗传性疾病，可导致对1α，25-二羟基维生素D_3 [1α，25(OH)_2D_3]的抗性。研究发现，A环修饰的类似物2α-（3-羟丙基）和2α-（3-羟丙基）-1α,25(OH)_2D_3、（O1C3和O2C3）与突变体VDR （R274A）结合效果优于天然激素，与HVDRR突变体R274L相似，突变体VDR （R274A）失去了1α，25(OH)_2D_3的1α-羟基氢键。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.