title: Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database.
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 Kivalue 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.
authors.affiliation: Computer Chemistry Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052 Erlangen, Germany.|Food Chemistry Unit, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sommer
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr-el-Aini Street, Cairo, P. O. Box 11562, Egypt.|Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr-el-Aini Street, Cairo, P. O. Box 11562, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Kerdawy
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Food Chemistry Unit, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Pischetsrieder
authors.affiliation: Computer Chemistry Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052 Erlangen, Germany.
authors.forename: Timothy
authors.initials: T
authors.lastname: Clark
mesh_terms: D001515:Beer; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*; D014439:Tyramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; D000242:Cyclic AMP; C007964:hordenine; D014439:Tyramine