Attenuating pregnane X receptor (PXR) activation: A molecular modelling approach
Attenuating pregnane X receptor (PXR) activation: A molecular modelling approach
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DOI：
10.1080/00498250601050412
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发表时间：
2007-02-01
期刊：
影响因子：
1.8
通讯作者：
Mosley, R. T.
中科院分区：
文献类型：
--
作者：
Gao, Y. -D.;Olson, S. H.;Mosley, R. T.
最近的研究表明，孕烷X受体（PXR）是细胞色素P450 3A（例如人类的CYP 3A 4）基因表达的关键调节因子。因此，PXR的激活可能导致CYP 3A 4蛋白的过度表达。由于CYP 3A 4的诱导可能导致临床上重要的药物-药物相互作用，因此在药物发现计划中，人们对降低候选药物激活PXR的可能性非常感兴趣。为了提供减弱候选药物介导的PXR激活的结构洞察，我们使用对接方法来研究PXR激活剂的结构-活性关系。基于我们的对接模型，有人提出，引入极性基团的激活剂的末端应减少其人PXR（hPXR）的活性，通过不稳定的相互作用，在疏水区的PXR配体结合口袋。然后设计并合成了许多包含这些结构特征的类似物，它们在反式激活试验中表现出显著较低的hPXR激活，并在基于人肝细胞的试验中表现出降低的CYP 3A 4诱导。此外，提供了一个实例，其中通过使受体的螺旋11和12空间不稳定来实现减弱hPXR活化。
Recent studies have demonstrated that the pregnane X receptor (PXR) is a key regulator of cytochromes P450 3A (e.g. CYP3A4 in human) gene expression. As a result, activation of PXR may lead to CYP3A4 protein over-expression. Because induction of CYP3A4 could result in clinically important drug-drug interactions, there has been a great interest in reducing the possibility of PXR activation by drug candidates in drug-discovery programmes. In order to provide structural insight for attenuating drug candidate-mediated PXR activation, we used a docking approach to study the structure-activity relationship for PXR activators. Based on our docking models, it is proposed that introducing polar groups to the end of an activator should reduce its human PXR (hPXR) activity via destabilizing interactions in the hydrophobic areas of the PXR ligand-binding pocket. A number of analogues that incorporate these structural features then were designed and synthesized, and they exhibited significantly lower hPXR activation in a transactivation assay and decreased CYP3A4 induction in a human hepatocytes-based assay. In addition, an example in which attenuating hPXR activation was achieved by sterically destabilizing the helices 11 and 12 of the receptor is presented.