title: The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14.
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.
authors.affiliation: 2The Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel. masha.niv@mail.huji.ac.il.
authors.forename: Anat
authors.initials: A
authors.lastname: Levit
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowak
authors.forename: Maximilian
authors.initials: M
authors.lastname: Peters
authors.forename: Ayana
authors.initials: A
authors.lastname: Wiener
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meyerhof
authors.forename: Maik
authors.initials: M
authors.lastname: Behrens
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship; D000098706:Taste Receptors, Type 2
chemical_list: D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2
keywords: GPCRs; cross-reactivity; drug repositioning; multispecificity