Gao Y D, Olson S H, Balkovec J M, Zhu Y, Royo I, Yabut J, Evers R, Tan E Y, Tang W, Hartley D P, Mosley R T
Department of Molecular Systems, Merck Research Laboratories, Madrid, Spain.
Xenobiotica. 2007 Feb;37(2):124-38. doi: 10.1080/00498250601050412.
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.
最近的研究表明，孕烷X受体（PXR）是细胞色素P450 3A（如人类中的CYP3A4）基因表达的关键调节因子。因此，PXR的激活可能导致CYP3A4蛋白过度表达。由于CYP3A4的诱导可能导致临床上重要的药物-药物相互作用，在药物研发项目中，人们对降低候选药物激活PXR的可能性产生了浓厚兴趣。为了提供有关减弱候选药物介导的PXR激活的结构见解，我们采用对接方法研究PXR激活剂的构效关系。基于我们的对接模型，有人提出在激活剂末端引入极性基团应通过破坏PXR配体结合口袋疏水区域的相互作用来降低其对人PXR（hPXR）的活性。随后设计并合成了许多具有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，并且在基于人肝细胞的试验中降低了CYP3A4的诱导。此外，还给出了一个通过空间位阻破坏受体的11和12螺旋来实现减弱hPXR激活的例子。
