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. 2017 Mar 10;7:44201.
doi: 10.1038/srep44201.

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

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Free PMC article

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

Thomas Sommer et al. Sci Rep. .
Free PMC article

Abstract

The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Schematic representation of the VS process from database generation to experimental testing.
The numbers on the left and on the right side represent the number of compounds that passed through the respective VS step depicted in the centre. Due to 230 compounds that are present in both FCDB and PhyDB, the absolute number of different compounds is smaller than the sum of the compounds in the two databases.
Figure 2
Figure 2
The overall best D2R-agonist pharmacophore and its inter-feature distances (a), depicted together with its ROC curve that results from VS of the test database (b). The features are hydrogen bond donor (purple, HBD), aromatic ring (orange, R) and positive ionisable (red, P). The dashed red line in the ROC plot indicates a random selection.
Figure 3
Figure 3
The overall best D2R-antagonist pharmacophore models and their inter-feature distances (a and b) depicted together with the corresponding ROC curves that result from VS of the test database (c). The features are hydrogen bond acceptor (green, HBA), aromatic ring (orange, R), positive ionisable (red, P) and hydrophobic (blue, H). The dashed red line in the ROC plot indicates a random selection. The blue curve corresponds to model a) and the green curve to model b).
Figure 4
Figure 4
Structures of the experimentally tested D2R-agonist (a) and -antagonist (b) VS hits. The 17 compounds can be classified into natural food constituents (delphinidin, hordenine, kukoamine A, pyrraline, salsolinol, roquefortine C), further compounds from natural sources (fumigaclavine A, leonurine, muscimol, ajmalicine, dihydroberberine, emetine), and food contaminants (clenbuterol, fenpropimorph, halofuginone, robenidine, sarafloxacin).
Figure 5
Figure 5. Receptor activation properties of hordenine.
In comparison to dopamine, hordenine shows agonist properties in the inhibition of forskolin-stimulated cAMP accumulation (a). While no β-arrestin-2 recruitment was determined for hordenine (b), the test substance completely antagonised quinpirole-stimulated recruitment (c).
Figure 6
Figure 6. Conformation of hordenine and its receptor-ligand interactions obtained after docking and energy minimisation.
We used an active-state homology model of D2R and performed MD simulations with the endogenous ligand dopamine. Dopamine was removed from the model, hordenine was docked into the binding pocket and the resulting receptor-ligand complex was subjected to energy minimisation in a water box. Whereas dopamine is able to form two hydrogen bonds with both Ser1935.42 and Ser1975.46 in the D2UpR model, our VS hit hordenine forms only a single hydrogen bond to Ser1975.46 due to the lack of a second hydroxyl group.

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