Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8‐Hydroxyefavirenz Exhibit Divergence in Activation,ChemMedChem

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Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8‐Hydroxyefavirenz Exhibit Divergence in Activation
ChemMedChem ( IF 3.6 ) Pub Date : 2018-03-02 , DOI: 10.1002/cmdc.201700730
Bhargavi Narayanan ₁ , Julie M Lade ₂ , Carley J S Heck ₂ , Kevin D Dietz ₁ , Herschel Wade ₁ , Namandjé N Bumpus ₃

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Efavirenz (EFV), an antiretroviral that interacts clinically with co‐administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8‐hydroxyEFV (8‐OHEFV) can activate PXR and potentially contribute to PXR‐mediated drug–drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8‐OHEFV does not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, by approximately 28‐fold in primary hepatocytes isolated from PXR‐humanized mice, whereas treatment with 8‐OHEFV did not result in a change in Cyp3A11 mRNA levels. FRET‐based competitive binding assays and isothermal calorimetry demonstrated that even with the lack of ability to activate PXR, 8‐OHEFV displays an affinity for PXR (IC₅₀ 12.1 μm; K_D 7.9 μm) nearly identical to that of EFV (IC₅₀ 18.7 μm; K_D 12.5 μm). The use of 16 EFV analogues suggest that other discreet changes to the EFV structure beyond the 8‐position are well tolerated. Molecular docking simulations implicate an 8‐OHEFV binding mode that may underlie its divergence in PXR activation from EFV.

中文翻译：

探究孕烷 X 受体 (PXR) 中的配体结构-活性关系：依非韦伦和 8-羟基依非韦伦在激活方面表现出差异

依法韦仑 (EFV) 是一种抗逆转录病毒药物，在临床上通过激活孕烷 X 受体 (PXR) 与联合用药发生相互作用，被细胞色素 P450 广泛代谢。我们测试了其主要代谢物 8-羟基EFV (8-OHEFV) 是否可以激活 PXR，并可能有助于 EFV 引起的 PXR 介导的药物间相互作用。荧光素酶报告基因检测显示，尽管 8-OHEFV 与 EFV 仅存在一个氧原子不同，但它不会激活 PXR。证实了这一点，在从 PXR 人源化小鼠中分离的原代肝细胞中，用 EFV 处理 72 小时，PXR 靶基因Cyp3a11的 mRNA 丰度提高了约 28 倍，而用 8-OHEFV 处理并没有导致 Cyp3A11 的变化mRNA 水平。基于 FRET 的竞争性结合测定和等温量热法表明，即使缺乏激活 PXR 的能力，8-OHEFV 对 PXR 的亲和力（IC ₅₀ 12.1 μm ； K _D 7.9 μm ）几乎与 EFV（IC 50 12.1 μm；K D 7.9 μm）相同。 ₅₀ 18.7微米； KD _12.5微米）。 16 个 EFV 类似物的使用表明 EFV 结构 8 位以外的其他谨慎变化具有良好的耐受性。分子对接模拟表明 8-OHEFV 结合模式可能是其 PXR 激活与 EFV 差异的基础。

更新日期：2018-03-02

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