The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14

Levit, Anat; Nowak, Stefanie; Peters, Maximilian; Wiener, Ayana; Meyerhof, Wolfgang; Behrens, Maik; Niv, Masha Y.

doi:10.1096/fj.13-242594

Cited by 107 publications

(103 citation statements)

References 81 publications

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“…23,24) Inhibition of hTAS2Rs, especially hTAS2R14, would be one approach to reducing the bitterness of drugs. To date, only a few bitter inhibitors have been discovered that block bittersubstance-evoked hTAS2R activation, such as Sakuranetin for hTAS2R31, 25,26) 6-methoxyflavanones for hTAS2R39, 27,28) γ-aminobutyric acid (GABA), N α ,N α -bis(carboxymethyl)-L-lysine (BCML) 29) and abscisic acid 30) for hTAS2R4, and (R)-Citronellal for hTAS2R43 and hTAS2R46.…”

Section: Discussionmentioning

confidence: 99%

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

et al. 2018

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The purpose of this study was to examine the ability of the artificial taste sensor to evaluate the bitterness of drugs by comparing the responses of the taste sensor with documented responses of human TASTE2 receptors (hTAS2Rs). For this purpose 22 bitter compounds, used as ingredients of pharmaceutical medicines in Japan and known ligands of hTAS2Rs, were selected for testing. Their solutions (0.01, 0.03, 0.1 mM) were evaluated by five different taste sensors (AC0, AN0, BT0, C00, AE1). Correlations between physicochemical parameters of the compounds and the responses of the taste sensors and hTAS2Rs were evaluated. From taste sensor measurements, diphenidol, haloperidol, diphenhydramine, dextromethorphan and papaverine, all ligands of hTAS2R 10 and/or hTAS2R14, were predicted to express strong bitterness, surpassing that of quinine. Responses of taste sensors BT0 were found to be significantly correlated with responses of hTAS2R14. High log P values (≧2.73) and responses of hTAS2R14 were also significantly correlated (** p<0.01, chi-square test). In conclusion, taste sensor BT0 is highly sensitive to bitterness and correlates significantly with hTAS2R14, making it useful for evaluating the bitterness of hydrophobic compounds which respond to hTAS2R14 and their inhibitors.

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Section: Discussionmentioning

confidence: 99%

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

et al. 2018

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“…Their protocol significantly improved the hit rate when compared with individual methods. Levit et al [48] integrated 1D molecular descriptors, 2D fingerprint-based molecular similarity, ligandbased pharmacophore models and a shape-based VS method to identify activators of human bitter taste receptor TAS2R14. The reported agonist activated both subtypes of liver X receptor (LXR a and b).…”

Section: Ligand Based Hlvs (Lb-hlvs)mentioning

confidence: 99%

Hierarchical virtual screening approaches in small molecule drug discovery

Kumar¹,

Zhang²

2015

Methods

135

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Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery.

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“…Despite promoting calcium mobilization, the bitter tastants decrease ASM cell stiffness, relax contracted ASM tissue from mice and humans, and decrease airway resistance in a murine model of asthma. The exact mechanism for this relaxant effect has been subject of debate (Deshpande, et al, 2010; Tan & Sanderson, 2014; Zhang, et al, 2013b), but bitter tastant receptors have nevertheless emerged as intriguing new therapeutic targets, with considerable efforts underway to synthesize new, more potent TAS2R agonists (Behrens & Meyerhof, 2013; Brockhoff, et al, 2010; Levit, et al, 2014). …”

Section: New Targetsmentioning

confidence: 99%

Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones

Pera

Penn

2016

Pharmacology & Therapeutics

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Despite over 50 years of inhaled beta-agonists and corticosteroids as the default management or rescue drugs for asthma, recent research suggests that new therapeutic options are likely to emerge. This belief stems from both an improved understanding of what causes and regulates airway smooth muscle (ASM) contraction, and the identification of new targets whose inhibition or activation can relax ASM. In this review we discuss the recent findings that provide new insight into ASM contractile regulation, a revolution in pharmacology that identifies new ways to “tune” G protein-coupled receptors to improve therapeutic efficacy, and the discovery of several novel targets/approaches capable of effecting bronchoprotection or bronchodilation.

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The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14

Cited by 107 publications

References 81 publications

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

Hierarchical virtual screening approaches in small molecule drug discovery

Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones

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