Fluorescent probes for rapid screening of potential drug-drug interactions at the CYP3A4 level

Antoinette Chougnet, Yelena Grinkova, David Ricard, Stephen Sligar, Wolf D. Woggon

Research output: Contribution to journalArticlepeer-review

Abstract

Steroid derivatives bearing fluorescent groups such as anthracene, dansyl, deazaflavin, and pyrene attached to C6 were synthesized. These compounds are unique inhibitors of cytochrome P450 3A4 (CYP3A4) and display similar IC 50 values in the μM range for the CYP3A4 substrates midazolam, testosterone, and nifedipine. On binding to CYP3A4, the fluorescence of the dansyl, deazaflavin, and pyrene probes is quenched by photophysical interaction of the fluorophore with the heme. The addition of drug candidates with binding constants in the nM-μM range causes displacement of the probes from the active site, and hence leads to restoration of fluorescence. Accordingly, relative affinities of drug candidates to CYP3A4 can be easily and accurately determined by fluorescence measurements.

Original languageEnglish (US)
Pages (from-to)717-724
Number of pages8
JournalChemMedChem
Volume2
Issue number5
DOIs
StatePublished - May 14 2007

Keywords

  • Cytochrome P450 3A4
  • Drug-drug interactions
  • Fluorescence
  • Inhibition
  • Porphyrins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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