Structure-guided discovery of high affinity TAS2R14 ligands

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TAS2Rs are G protein-coupled receptors (GPCRs) that mediate bitter taste recognition. There is accumulating evidence that these chemosensory receptors are also expressed in extraoral tissues. In particular, the subtype TAS2R14 was found in human airway smooth muscle and may be a novel drug target for airway diseases. A detailed understanding of bitter taste receptor biology as well as structural information on these receptors are still lacking The development of high affinity agonists and antagonists for TAS2R14 will enable biological, physiological and structural studies and may also have a significant impact on drug discovery. This project aims to develop such compounds by taking advantage of an intensive collaboration between the lab of Professor Peter Gmeiner in Germany with a long-standing experience in the discovery of GPCR ligands, and the lab of Professor Masha Niv in Israel, with strong expertise in computational approaches, in particular for bitter taste receptors and ligands. The design and synthesis of high affinity TAS2R14 ligands will be performed by a combination of approaches integrating library-based in vitro screening, docking of large in silico libraries and hit-to-lead optimization. We will use our screening hits to refine structural models of TAS2R14 for computational docking screens of multi-million molecule libraries with wide chemical space. A detailed pharmacological evaluation of hits in cell-based assays for G protein activation and beta-arrestin recruitment will provide novel insights into the signaling of the TAS2R family, particularly in view of the current appreciation of biased agonism in GPCRs. Hit-to-lead optimization and further structural modifications will give access to high affinity TAS2R14 ligands, a specific radioligand and covalent ligands that may be useful for the construction of stable receptor-ligand complexes. The newly developed TAS2R14 ligands will be of great interest for drug discovery, food science and structural biology.