Snooker structure-based pharmacophore model explains differences in agonist and blocker binding to bitter receptor hTAS2R39.
The human bitter taste receptor hTAS2R39 can be activated by many dietary (iso)flavonoids. Furthermore, hTAS2R39 activity can be blocked by 6-methoxyflavanones, 4'-fluoro-6-methoxyflavanone in particular. A structure-based pharmacophore model of the hTAS2R39 binding pocket was built using Snooker software, which has been used successfully before for drug design of GPCRs of the rhodopsin subfamily. For the validation of the model, two sets of compounds, both of which contained actives and inactives, were used: (i) an (iso)flavonoid-dedicated set, and (ii) a more generic, structurally diverse set. Agonists were characterized by their linear binding geometry and the fact that they bound deeply in the hTAS2R39 pocket, mapping the hydrogen donor feature based on T5.45 and N3.36, analogues of which have been proposed to play a key role in activation of GPCRs. Blockers lack hydrogen-bond donors enabling contact to the receptor. Furthermore, they had a crooked geometry, which could sterically hinder movement of the TM domains upon receptor activation. Our results reveal characteristics of hTAS2R39 agonist and bitter blocker binding, which might facilitate the development of blockers suitable to counter the bitterness of dietary hTAS2R39 agonists in food applications.
Laboratory of Food Chemistry, Wageningen University, 6708 WG Wageningen, The Netherlands.
Wibke S U
WS
Roland
Computational Discovery and Design Group (CDD), Centre for Molecular and Biomolecular Informatics (CMBI), Radboud university medical center, 6500 HB Nijmegen, The Netherlands.
Marijn P A
MP
Sanders
Unilever R&D, 3133 AT Vlaardingen, The Netherlands.
Leo
L
van Buren
Unilever R&D, 3133 AT Vlaardingen, The Netherlands.
Robin J
RJ
Gouka
Laboratory of Food Chemistry, Wageningen University, 6708 WG Wageningen, The Netherlands.
Harry
H
Gruppen
Laboratory of Food Chemistry, Wageningen University, 6708 WG Wageningen, The Netherlands.
Jean-Paul
JP
Vincken
Computational Discovery and Design Group (CDD), Centre for Molecular and Biomolecular Informatics (CMBI), Radboud university medical center, 6500 HB Nijmegen, The Netherlands.
Tina
T
Ritschel
D001665:Binding Sites; D015195:Drug Design; D044950:Flavanones / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012984:Software
C000598908:6-methoxyflavanone; D044950:Flavanones; D005419:Flavonoids; D011956:Receptors, Cell Surface; C557300:TAS2R39 protein, human