The bitter pill: Clinical drugs that activate the human bitter taste receptor TAS2R14

Anat Levit, Stefanie Nowak, Maximilian Peters, Ayana Wiener, Wolfgang Meyerhof, Maik Behrens, Masha Y. Niv

Research output: Contribution to journalArticlepeer-review

Abstract

Bitter taste receptors (TAS2Rs) mediate aversive response to toxic food, which is often bitter. These G-protein-coupled receptors are also expressed in extraoral tissues, and emerge as novel targets for therapeutic indications such as asthma and infection. Our goal was to identify ligands of the broadly tuned TAS2R14 among clinical drugs. Molecular properties of known human bitter taste receptor TAS2R14 agonists were incorporated into pharmacophore- and shape-based models and used to computationally predict additional ligands. Predictions were tested by calcium imaging of TAS2R14- transfected HEK293 cells. In vitro testing of the virtual screening predictions resulted in 30-80% success rates, and 15 clinical drugs were found to activate the TAS2R14. hERG potassium channel, which is predominantly expressed in the heart, emerged as a common off-target of bitter drugs. Despite immense chemical diversity of known TAS2R14 ligands, novel ligands and previously unknown polypharmacology of drugs were unraveled by in vitro screening of computational predictions. This enables rational repurposing of traditional and standard drugs for bitter taste signaling modulation for therapeutic indications.

Original languageAmerican English
Pages (from-to)1181-1197
Number of pages17
JournalFASEB Journal
Volume28
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • Cross-reactivity
  • Drug repositioning
  • GPCRs
  • Multispecificity

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Biochemistry
  • Biotechnology

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