Structure-based design of selective agonists for a rickets-associated mutant of the vitamin d receptor.
Structure-based design of selective agonists for a rickets-associated mutant of the vitamin d receptor.
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DOI：
10.1021/ja0268377
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发表时间：
2002-10
影响因子：
15
通讯作者：
S. Swann;J. Bergh;M. Farach-Carson;Cory A. Ocasio;J. Koh
中科院分区：
文献类型：
--
作者：
S. Swann;J. Bergh;M. Farach-Carson;Cory A. Ocasio;J. Koh
核和类固醇激素受体作为与发育和稳态相关的不同基因组的配体依赖性转录调节因子发挥作用。维生素D受体（VDR）是核和类固醇激素受体家族的成员，其突变与人类维生素D抵抗性佝偻病（hVDRR）有关，并导致血清1，25（OH）（2）D（3）浓度升高和严重的骨发育不良。几种hVDR相关突变体已定位于VDR的配体结合结构域，并导致配体结合和配体依赖性反式激活功能的减少或丧失。错义突变Arg 274--> Leu导致1，25（OH）（2）D（3）反应性降低>1000倍，因此不再受激素生理浓度的调节。在这项研究中，计算机辅助分子设计被用来生成VDR激动剂LG 190155的非甾体类似物的集中文库，这些非甾体类似物被独特地设计为补充与hVDRR相关的Arg 274-> Leu。设计的类似物中有一半在hVDRR相关突变体中表现出显著的活性，而结构相似的对照化合物中没有一种表现出显著的活性。在突变受体中，7种最具活性的设计类似物的效力比1，25（OH）（2）D（3）高16至526倍（EC（50）= 3.3-121 nM）。值得注意的是，类似物对核VDR具有选择性，并且不刺激细胞钙内流，这与膜相关维生素D受体的激活有关。
The nuclear and steroid hormone receptors function as ligand-dependent transcriptional regulators of diverse sets of genes associated with development and homeostasis. Mutations to the vitamin D receptor (VDR), a member of the nuclear and steroid hormone receptor family, have been linked to human vitamin D-resistant rickets (hVDRR) and result in high serum 1,25(OH)(2)D(3) concentrations and severe bone underdevelopment. Several hVDRR-associated mutants have been localized to the ligand binding domain of VDR and cause a reduction in or loss of ligand binding and ligand-dependent transactivation function. The missense mutation Arg274 --> Leu causes a >1000-fold reduction in 1,25(OH)(2)D(3) responsiveness and is, therefore, no longer regulated by physiological concentrations of the hormone. In this study, computer-aided molecular design was used to generate a focused library of nonsteroidal analogues of the VDR agonist LG190155 that were uniquely designed to complement the Arg274 --> Leu associated with hVDRR. Half of the designed analogues exhibit substantial activity in the hVDRR-associated mutant, whereas none of the structurally similar control compounds exhibited significant activity. The seven most active designed analogues were more than 16 to 526 times more potent than 1,25(OH)(2)D(3) in the mutant receptor (EC(50) = 3.3-121 nM). Significantly, the analogues are selective for the nuclear VDR and did not stimulate cellular calcium influx, which is associated with activation of the membrane-associated vitamin D receptor.