Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

• DOI: 10.1101/2022.11.24.517821
• Publication Date: 2022-11-25T17:58:35Z
• Authors: Fabrizio Fierro; Lior Peri; Harald Hübner; Alina Tabor-Schkade; Lukas Waterloo; Stefan Löber; Tara Pfeiffer; Dorothee Weikert; Tamir Dingjan; Eitan Margulis; Peter Gmeiner; Masha Y Niv
• Keywords: Chemical library; Bitter Taste

Abstract The human GPCR family comprises circa 800 members, activated by hundreds of thousands compounds. Bitter taste receptors, TAS2Rs, constitute a large and distinct subfamily, expressed orally extra-orally involved in physiological pathological conditions. TAS2R14 is the most promiscuous member, with over 150 agonists 3 antagonists known prior to this study. Due scarcity inhibitors importance chemical probes for exploring functions, we aimed discover new ligands receptor, emphasis on antagonists. To cope lack experimental structure used mixed experimental/computational methodology which iteratively improved performance predicted structure. increasing number active compounds, obtained here through screening FDA-approved drug library, chemically synthesized flufenamic acid derivatives, enabled refinement binding pocket, turn structure-based virtual reliability. This approach led identification 10 200 TAS2R14, illustrating untapped potential rigorous medicinal chemistry TAS2Rs. iterative framework suggested residues activation process, suitable expanding bitter bitter-masking space, applicable other GPCRs lacking structures. Graphical abstract