Probing Ligand Structure-Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation.

Autor: Narayanan B; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Hunterian 709, Baltimore, MD, USA., Lade JM; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Biophysics 307, Baltimore, MD, USA., Heck CJS; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Biophysics 307, Baltimore, MD, USA., Dietz KD; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Hunterian 709, Baltimore, MD, USA., Wade H; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Hunterian 709, Baltimore, MD, USA., Bumpus NN; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Biophysics 307, Baltimore, MD, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2018 Apr 06; Vol. 13 (7), pp. 736-747. Date of Electronic Publication: 2018 Mar 02.
DOI: 10.1002/cmdc.201700730
Abstrakt: 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 (IC 50 12.1 μm; K D 7.9 μm) nearly identical to that of EFV (IC 50 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.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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