Taste, drugs and toxicity

Bitter taste sensation is innately aversive, can be elicited by numerous and chemically diverse molecules¹ and is typically thought to protect against consuming poisons. However, our recent quantitative analysis suggests only a weak association between bitterness and toxicity.² Furthermore, the receptors for bitter taste (T2Rs), a subfamily of G-protein coupled receptors, were found to be expressed both orally and extra-orally, and are proposed as novel therapeutic targets for several indications.

Many clinical drugs elicit bitter taste, suggesting the possibility of drug re-purposing for T2R-mediated activity. On the other hand, the bitter taste of medicine presents a major compliance problem for pediatric drugs, and in these cases T2Rs represent undesirable off-targets.³

A toolbox of computational approaches for prediction of bitterness intensity, ligand-T2R subtype assignment and agonist/antagonist pharmacology is presented, followed by confirmations using cell-based functional assays. Implications of the results are discussed in view of drug polypharmacology, and involvement of T2R subtypes in pancreatic cancer chemoresistance.

1. Dagan-Wiener, A. et al. BitterDB: taste ligands and receptors database in 2019. Nucleic acids research 47, D1179-D1185 (2019).
2. Nissim, I., Dagan-Wiener, A. & Niv, M.Y. The taste of toxicity: A quantitative analysis of bitter and toxic molecules. IUBMB Life 69, 938-946 (2017).
3. Bahia, M.S., Nissim, I. & Niv, M.Y. Bitterness prediction in-silico: A step towards better drugs. Int J Pharm 536, 526-529 (2018).