Snooker structure-based pharmacophore model explains differences in agonist and blocker binding to bitter receptor hTAS2R39

PloS One
Wibke S U RolandTina Ritschel

Abstract

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 hTAS2R3...Continue Reading

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Citations

Jul 6, 2016·Bioscience, Biotechnology, and Biochemistry·Yuki KurodaTatsuo Watanabe
Apr 2, 2017·International Journal of Pharmaceutics·Malkeet Singh BahiaMasha Y Niv
Sep 7, 2019·Current Opinion in Clinical Nutrition and Metabolic Care·Marie-Chantal Canivenc-LavierLoïc Briand
Dec 20, 2018·Journal of Chemical Information and Modeling·Viet-Khoa Tran-NguyenDidier Rognan

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Software Mentioned

Snooker
MOE

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