Ligand-protein interactions are the basis of all biological processes in our body, including flavor perception. Smell and taste are mediated by G protein-coupled receptors (GPCRs), trans-membrane proteins highly studied for drug discovery. Olfactory (ORs) and bitter taste receptors (TAS2Rs) constitute the first and third largest GPCR groups. Interestingly, smell and taste receptors are ‘ec-nomo-topically’ [out-of-the-usual-place] expressed, they are found to be involved in many physiological/pathological functions other than chemosensation, and are therefore suggested as targets for pharmaceutical intervention. TAS2R14 is one of the most broadly tuned bitter taste receptors and is activated by chemically diverse natural and synthetic compounds. Half of the compounds perceived bitter by humans may elicit bitterness by activating this receptor. TAS2R14 antagonists’ discovery is an increasing market opportunity to attenuate bitterness perception and improve palatability and preference among consumers. Moreover, this receptor has biological roles related to innate immune responses, male fertility, and cancer. TAS2R14 modulators have the potential to efficiently shed light on extra-oral functions and attempt to treat TAS2R14-mediated pathological disorders. To the best of my knowledge, TAS2R14 has been the first chemosensory receptor used as a target for a computational-driven hit optimization study. Flufenamic acid, the most potent and selective agonist for TAS2R14, was used as the lead structure. Knowledge-based homology modeling has led to a validated agonist-bound conformation of the TAS2R14 binding site. A virtual combinatorial library of ~1000 flufenamic acid derivatives was generated and docked to the TAS2R14 model. Out of the 19 synthesized and tested compounds, 15 new TAS2R14 ligands were identified: interestingly, we found agonists with improved potency compared to flufenamic acid and compounds with high potency but with partial agonist/partial antagonist properties. This work suggests that computational flavor chemistry may, therefore, speed up the process of hit identification and optimization for chemosensory GPCRs, providing the tools to decode the complex receptor-based mechanisms underlying chemosensation, but also to illuminate the ecnomotopic chemosensory GPCRs’ molecular pharmacology.

Computational flavor chemistry: Towards the rational design of chemosensory GPCR-targeted food ingredients and drug candidates

2019 Fall National Meeting

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