Human pregnane X receptor antagonists and Agonists define molecular requirements for different binding sites
Human pregnane X receptor antagonists and Agonists define molecular requirements for different binding sites
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DOI：
10.1124/mol.107.038398
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发表时间：
2007-09-01
影响因子：
3.6
通讯作者：
Bachmann, Kenneth
中科院分区：
文献类型：
--
作者：
Ekins, Sean;Chang, Cheng;Bachmann, Kenneth
妊娠X受体（PXR）是外源代谢和转运基因表达的重要转录调控因子。受体是混杂的，结合许多结构类型的分子，在配体结合区域充当激动剂，触发基因上调，增加治疗药物的代谢和排泄，并引起药物-药物相互作用。有人认为，人类PXR拮抗剂代表了一种抵消这种相互作用的手段。当激动剂同时结合在配体结合区域时，假设有几种氮唑结合在PXR外部的活化功能- 2 （AF- 2）表面。在本研究中，我们使用不同系列的咪唑、类固醇和一组不同的分子，根据PXR激动剂的实验结合数据，推导了新的PXR激动剂的计算模型。我们还为类固醇激动剂位点定义了一种新的药效团。所有激动剂药效团均表现出疏水特征。相比之下，与使用偶氮和联苯的相应PXR拮抗剂药效团模型进行定性比较表明，它们更小，疏水，更强调氢键特征。唑类拮抗剂被停靠在AF- 2位点外表面的疏水结合口袋中，并舒适地安装，与参与电荷夹紧的关键氨基酸相互作用。结合不同类别分子的计算和实验数据，为激动剂和拮抗剂结合PXR的不同区域提供了强有力的证据。这些观察结果对未来发现更具选择性和更有效的拮抗剂分子具有重要意义。
The pregnane X receptor ( PXR) is an important transcriptional regulator of the expression of xenobiotic metabolism and transporter genes. The receptor is promiscuous, binding many structural classes of molecules that act as agonists at the ligand- binding domain, triggering up- regulation of genes, increasing the metabolism and excretion of therapeutic agents, and causing drug- drug interactions. It has been suggested that human PXR antagonists represent a means to counteract such interactions. Several azoles have been hypothesized to bind the activation function- 2 ( AF- 2) surface on the exterior of PXR when agonists are concurrently bound in the ligand- binding domain. In the present study, we have derived novel computational models for PXR agonists using different series of imidazoles, steroids, and a set of diverse molecules with experimental PXR agonist binding data. We have additionally defined a novel pharmacophore for the steroidal agonist site. All agonist pharmacophores showed that hydrophobic features are predominant. In contrast, a qualitative comparison with the corresponding PXR antagonist pharmacophore models using azoles and biphenyls showed that they are smaller and hydrophobic with increased emphasis on hydrogen bonding features. Azole antagonists were docked into a proposed hydrophobic binding pocket on the outer surface at the AF- 2 site and fitted comfortably, making interactions with key amino acids involved in charge clamping. Combining computational and experimental data for different classes of molecules provided strong evidence for agonists and antagonists binding distinct regions on PXR. These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists.