The typical bitter taste of beer is caused by adding hops (Humulus lupulus L.) during the wort boiling process. The bitter taste of hop-derived compounds was found to be mediated by three bitter taste receptors: TAS2R1, TAS2R14, and TAS2R40. In this work, structural bioinformatics analyses were used to characterize the binding modes of trans-isocohumulone, trans-isohumulone, trans-isoadhumulone, cis-isocohumulone, cis-isohumulone, cis-isoadhumulone, cohumulone, humulone, adhumulone, and 8-prenylnaringenin into the orthosteric binding site of their cognate receptors. A conserved asparagine in transmembrane 3 was found to be essential for the recognition of hop-derived compounds, whereas the surrounding residues in the binding site of the three receptors encode the ligand specificity. Hop-derived compounds are renowned bioactive molecules and are considered as potential hit molecules for drug discovery to treat metabolic diseases. A chemoinformatics analysis revealed that hop-derived compounds cluster in a different region of the chemical space compared to known bitter food-derived compounds, pinpointing hop-derived compounds as a very peculiar class of bitter compounds.
Keywords: GPCRs; beer; bitter taste; chemical space; diabetes; hops; molecular modeling.