Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands.
Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands.
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DOI：
10.1016/j.cbi.2010.09.018
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发表时间：
2010-12-05
影响因子：
5.1
通讯作者：
Stoner, Matthew A.
中科院分区：
文献类型：
--
作者：
Dring, Ann M.;Anderson, Linnea E.;Qamar, Saima;Stoner, Matthew A.
组成型雄烷受体（CAR）和雄烷X受体（PXR）是密切相关的孤儿核受体蛋白，其共享几个配体并靶向参与稳态和药物代谢的所有阶段的重叠基因组。CAR和PXR参与某些疾病的发展，包括糖尿病、代谢综合征和肥胖症。到目前为止，这些受体的配体筛选通常集中在基于药效团的方法的类固醇激素类似物上，只发现相对较少的新命中。已在人肝脏中检测到多种CAR亚型，其中最丰富的是组成型活性参照CAR 1和配体依赖性亚型CAR 3。据推测，任何结合CAR 1的化合物也应该激活CAR 3，因此CAR 3可以用作CAR 1研究的配体激活替代物。到目前为止，CAR 3特异性配体的可能性尚未得到解决。为了研究CAR 1、CAR 3和PXR之间的差异，并寻找更多可能用于定量结构-活性关系（QSAR）研究的CAR配体，我们对60种主要为非类固醇化合物进行了荧光素酶反式激活试验筛选。选择具有不同核心化学的已知活性化合物作为起始点，并合理选择结构变体用于筛选。在49种化合物中观察到激动剂与反向激动剂/拮抗剂作用的明显差异，这些化合物对至少一种受体具有一定的配体作用，18种化合物对所有三种受体都有作用; 8种化合物仅为CAR 1配体，3种化合物仅为CAR 3配体，4种化合物仅影响PXR。这项工作为新的CAR配体提供了证据，其中一些配体具有CAR 3特异性作用，并提供了关于CAR和PXR配体的观察数据，以便为计算机策略提供信息。对任何一种受体表现出独特活性的化合物是用于研究体内分子靶标的潜在有价值的诊断工具。
Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets.
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DOI：
10.1161/01.atv.0000146530.24736.ce
发表时间：
2004-12-01
影响因子：
8.7
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0630614100
发表时间：
2003-04-01
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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