Discovery of 2-Aminopyrimidines as Potent Agonists for the Bitter Taste Receptor TAS2R14

Waterloo, Lukas; Hübner, Harald; Fierro, Fabrizio; Pfeiffer, Tara; Brox, Regine; Löber, Stefan; Weikert, Dorothée; Niv, Masha Y.; Gmeiner, Peter

doi:10.1021/acs.jmedchem.2c01997

Cited by 8 publications

(6 citation statements)

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“…Novel TAS2R14 agonists from recent publications were also included. , Due to the fact that the activation of only one TAS2R14 receptor was investigated, those compounds that have not been experimentally confirmed as agonists cannot be labeled as “nonbitter” since they may activate other TAS2Rs. Thus, 261 bitter compounds that are TAS2R14 agonists were added.…”

Section: Methodsmentioning

confidence: 99%

BitterMasS: Predicting Bitterness from Mass Spectra

Ziaikin,

Tello,

Peterson

et al. 2024

J. Agric. Food Chem.

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Bitter compounds are common in nature and among drugs. Previously, machine learning tools were developed to predict bitterness from the chemical structure. However, known structures are estimated to represent only 5−10% of the metabolome, and the rest remain unassigned or "dark". We present BitterMasS, a Random Forest classifier that was trained on 5414 experimental mass spectra of bitter and nonbitter compounds, achieving precision = 0.83 and recall = 0.90 for an internal test set. Next, the model was tested against spectra newly extracted from the literature 106 bitter and nonbitter compounds and for additional spectra measured for 26 compounds. For these external test cases, BitterMasS exhibited 67% precision and 93% recall for the first and 58% accuracy and 99% recall for the second. The spectrum−bitterness prediction strategy was more effective than the spectrum−structure−bitterness prediction strategy and covered more compounds. These encouraging results suggest that BitterMasS can be used to predict bitter compounds in the metabolome without the need for structural assignment of individual molecules. This may enable identification of bitter compounds from metabolomics analyses, for comparing potential bitterness levels obtained by different treatments of samples and for monitoring bitterness changes overtime.

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Section: Methodsmentioning

confidence: 99%

BitterMasS: Predicting Bitterness from Mass Spectra

Ziaikin,

Tello,

Peterson

et al. 2024

J. Agric. Food Chem.

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“…In addition to their traditional gustatory roles, TAS2Rs are expressed in extraoral tissues, revealing a spectrum of potential functions that extend beyond bitter tasting 9,10 . Among the 25 TAS2Rs, TAS2R14 is a receptor of particular interest due to its promiscuity, responding to a variety of agonists with diverse structures 1,11 . Intriguingly, many clinical drugs evoke bitter taste responses, with approximately 9% of tested pharmaceutical drugs activating TAS2R14 2,3 .…”

Section: Introductionmentioning

confidence: 99%

“…Among the known TAS2R14 agonists, flufenamic acid (FFA) and aristolochic acid (AA) are two well-characterized activators with suitable potency 1,2,19 . FFA, a nonsteroidal anti-inflammatory drug 20 , and AA, a potent nephrotoxin produced by Aristolochia plant 21 , are intriguing examples of diverse chemical structures capable of binding to TAS2R14.…”

Section: Introductionmentioning

confidence: 99%

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Unlocking TAS2R14 activation through intricate multi-ligand binding networks

Hu,

Ao,

Gao

et al. 2024

Preprint

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Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1-3. In addition, TAS2R14 has broad expression in non-gustatory tissues, suggesting its important roles in selective physiological processes and therapeutic potential4. Here, we present cryo-electron microcopy structures of TAS2R14 in complex with flufenamic acid and aristolochic acid, coupling with G protein subtypes gustducin and Gi. Distinct from most known GPCRs, agonists of TAS2R14 bind to multiple intracellular pockets. We highlight the cholesterol molecules occupying an upper transmembrane site, typically the orthosteric pocket in other GPCRs, also binding in the entrance to an intracellular agonist binding pocket, suggesting an endogenous modulatory function5. The structural and mutagenesis analysis illuminate the receptor's broad-spectrum ligand recognition and activation via intricate multiple ligand-binding sites. Furthermore, we unveil the structural configuration of gustducin and its interaction with TAS2R14, as well as the coupling mode of Gi1. This investigation should be instrumental in advancing our knowledge of the mechanisms underlying bitter taste recognition and response, with broader relevance to sensory biology and pharmacology.

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“…Diarylamines are key scaffolds in medicinal chemistry, organic synthesis, and material science . Well-developed Buchwald–Hartwig, Chan–Lam–Evans or Ullmann-type C–N cross-coupling reactions utilizing anilines as nitrogen sources have emerged as powerful strategies to prepare diarylamines but commonly require high temperatures and elegantly designed complex ligands.…”

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confidence: 99%