Probing ligand structure-activity relationships in pregnane X receptor (PXR): efavirenz and 8-hydroxyefavirenz exhibit divergence in activation
| Autor: | Julie M. Lade, Bhargavi Narayanan, Kevin D. Dietz, Herschel Wade, Namandjé N. Bumpus, Carley J. S. Heck |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cyclopropanes Efavirenz Ligands Biochemistry digestive system Article 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Animals Humans General Pharmacology Toxicology and Pharmaceutics Receptor IC50 Pharmacology Pregnane X receptor Binding Sites biology Molecular Structure Organic Chemistry Pregnane X Receptor Cytochrome P450 Isothermal titration calorimetry Ligand (biochemistry) Molecular biology digestive system diseases Benzoxazines Molecular Docking Simulation 030104 developmental biology chemistry Nuclear receptor Alkynes biology.protein Hepatocytes Molecular Medicine Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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