Combining cell-based and computational methods to unravel TAS2R14 novel bitter receptor inhibitors

There are 25 bitter taste receptors (TAS2Rs) in the human body, which belong to the G-protein coupled receptors (GPCRs). There has been much interest in taste receptors in general and in TAS2R14, a bitter taste receptor expressed both orally and extra-orally. Bitter taste has a strong influence on food and drugs acceptance, thus, finding novel antagonists may serve as potential bitter taste masking agents, while novel agonists may be relevant for therapeutic applications. Bitter masking is a challenging area in the field of taste; numerous agonists (ligands that activate the receptor) were found but almost no antagonists (ligands that inhibit the receptor) are known yet.

We established a functional TAS2R14 cell-based system that detects the receptor-ligand complex activation by measuring the formation of myo-Inositol 1 phosphate (IP1), a downstream metabolite in the Gαq signal transduction pathway.

As part of this study, we perform a cell-based testing of computationally predicted candidates and use it to improve the TAS2R14 models, which are then used iteratively to predict additional ligands. The blocking or activating effects of tested compounds were measured in-vitro by measuring IP1 accumulation in the cells. Among these tested compounds, we discovered numerous newly agonists, and antagonists of TAS2R14. The novel agonists are suggested to be TAS2R14-specific using the BitterMatch classifier.

Using cell-based assays to study bitter taste receptor pharmacology, we will gain a better understanding of bitter taste receptor biology, and therefore, provide insight into the chemosensory G-protein coupled receptor family that has lacked experimental structure to date.