Design of drugs for Vitamin D receptor mutant related to hereditary vitamin D-resistant rickets

遗传性维生素D抵抗性佝偻病(HVDRR)是一种由维生素D受体突变引起的遗传性疾病，导致对1a,25-二羟基维生素D_3[1a,25(OH)_2D_3]产生抵抗。我们发现A环修饰的类似物2a-(3-羟丙基)-和2a-(3-羟丙氧基)-1a,25(OH)_2D_3,（O1C3和O2C3）比天然激素能更好地与突变体VDR（R274A）结合，与HVDRR突变体R274L相似，它失去了与1a-羟基的氢键1a,25(OH)_2D_3,。

Hereditary vitamin D-resistant rickets(HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1a,25-dihydroxyvitamin D_3[1a,25(OH)_2D_3]. We found that the A ring-modified analogues, 2a-(3-hydroxypropyl)- and 2a-(3-hydroxypropoxy)- 1a,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 1a-hydroxyl group of 1a,25(OH)_2D_3,.