Promiscuity and selectivity of bitter molecules and their receptors

Pizio, Antonella Di; Niv, Masha Y.

doi:10.1016/j.bmc.2015.04.025

Cited by 104 publications

(104 citation statements)

References 53 publications

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“…In summary, the current work demonstrated that chemical modification of TAS2R14 agonists allows to probe the spatial capacity of the binding pocket: the receptor TAS2R14 is able to accommodate agonists with a wide range of sizes, as typical for multispecific GPCRs (36), indicating that agonist-receptor contact points do not envelop the ligand tightly. This is in agreement with the finding that TAS2R promiscuity correlates with the binding site surface (37). Future work elucidating the contact points between TAS2R14 binding site residues and its agonists is necessary to reveal the molecular basis for the promiscuity of this receptor aside from its apparent spacious ligand binding site.…”

Section: Discussionsupporting

confidence: 85%

Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists

et al. 2016

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Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of (˜) 25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds.

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Section: Discussionsupporting

confidence: 85%

Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists

et al. 2016

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“…The fact that greater concentrations of the ligands were able to cause GLP-1 release with decreased receptor expression indicates that either these ligands also interact with other receptors to cause GLP-1 release or that only a small fraction of receptors are necessary to provide a full response. The former is consistent with the knowledge compiled on bitter taste receptors and their ligands about the promiscuity of these receptors and their ligands [41]. The fact that Z7 molecule caused GLP-1 responses provides a strong validation of our computational modeling methods for discovering novel ligands.…”

Section: Resultssupporting

confidence: 83%

A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells

Pham

Hui

Morvaridi

et al. 2016

Biochemical and Biophysical Research Communications

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The bitter taste receptor TAS2R38 is a G protein coupled receptor (GPCR) that has been found in many extra-oral locations like the gastrointestinal (GI) system, respiratory system, and brain, though its function at these locations is only beginning to be understood. To probe the receptor’s potential metabolic role, immunohistochemistry of human ileum tissues was performed, which showed that the receptor was co-localized with glucagon-like peptide 1 (GLP-1) in L-cells. In a previous study, we had modeled the structure of this receptor for its many taste-variant haplotypes (Tan et al. 2011), including the taster haplotype PAV. The structure of this haplotype was then used in a virtual ligand screening pipeline using a collection of ~2.5 million purchasable molecules from the ZINC database. Three compounds (Z7, Z3, Z1) were purchased from the top hits and tested along with PTU (known TAS2R38 agonist) in in vitro and in vivo assays. The dose-response study of the effect of PTU and Z7 on GLP-1 release using wild-type and TAS2R38 knockout HuTu-80 cells showed that the receptor TAS2R38 plays a major role in GLP-1 release due to these molecules. In vivo studies of PTU and the three compounds showed that they each increase GLP-1 release. PTU was also chemical linked to cellulose to slow its absorption and when tested in vivo, it showed an enhanced and prolonged GLP-1 release. These results suggest that the GI lumen location of TAS2R38 on the L-cell makes it a relatively safe drug target as systemic absorption is not needed for a TAS2R38 agonist drug to effect GLP-1 release.

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“…[29,30] The functional screening of human TAS2Rs has so far resulted in the identification of bitter agonists for 21 of the 25 receptors Moreover, it became evident that TAS2Rs recognize a highly variable number of structurally diverse bitter compounds ranging from single or few compounds to dozens. [31][32][33][34] These differences in tuning breadths suggest that receptors may contribute disproportionally to human bitter sensing. Among the three most broadly tuned receptors, TAS2R10, [35] TAS2R14, [36] and TAS2R46, [37] the TAS2R14 exhibits to date the largest panel of identified bitter agonists, which frequently represent drugs with profound pharmacological activities.…”

Section: Introductionmentioning

confidence: 99%

“…[28] On the tongue, subsets of TAS2R genes are co-expressed in bitter taste receptor cells that represent a subpopulation of type II cells within taste buds. [31][32][33][34] These differences in tuning breadths suggest that receptors may contribute disproportionally to human bitter sensing. [31][32][33][34] These differences in tuning breadths suggest that receptors may contribute disproportionally to human bitter sensing.…”

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confidence: 99%

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

et al. 2018

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A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.

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Promiscuity and selectivity of bitter molecules and their receptors

Cited by 104 publications

References 53 publications

Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists

Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists

A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

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