Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8‐Hydroxyefavirenz Exhibit Divergence in Activation |
| |
| Authors: | Bhargavi Narayanan Dr Julie M Lade Carley J S Heck Kevin D Dietz Dr Herschel Wade Dr Namandjé N Bumpus |
| |
| Affiliation: | 1. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA;3. Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA |
| |
| Abstract: | 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 ; KD 7.9 μm ) nearly identical to that of EFV (IC50 18.7 μm ; KD 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. |
| |
| Keywords: | cytochrome P450 drug metabolism ligand binding molecular docking nuclear receptors |
|
|
