2The Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
FASEB J. 2014 Mar;28(3):1181-97. doi: 10.1096/fj.13-242594. Epub 2013 Nov 27.
Bitter taste receptors (TAS2Rs) mediate aversive response to toxic food, which is often bitter. These G-protein-coupled receptors are also expressed in extraoral tissues, and emerge as novel targets for therapeutic indications such as asthma and infection. Our goal was to identify ligands of the broadly tuned TAS2R14 among clinical drugs. Molecular properties of known human bitter taste receptor TAS2R14 agonists were incorporated into pharmacophore- and shape-based models and used to computationally predict additional ligands. Predictions were tested by calcium imaging of TAS2R14-transfected HEK293 cells. In vitro testing of the virtual screening predictions resulted in 30-80% success rates, and 15 clinical drugs were found to activate the TAS2R14. hERG potassium channel, which is predominantly expressed in the heart, emerged as a common off-target of bitter drugs. Despite immense chemical diversity of known TAS2R14 ligands, novel ligands and previously unknown polypharmacology of drugs were unraveled by in vitro screening of computational predictions. This enables rational repurposing of traditional and standard drugs for bitter taste signaling modulation for therapeutic indications.
苦味受体（TAS2Rs）介导对有毒食物的厌恶反应，而这些食物通常是苦的。这些 G 蛋白偶联受体也在口腔外组织中表达，并成为治疗哮喘和感染等疾病的新靶点。我们的目标是在临床药物中鉴定广泛调节的 TAS2R14 的配体。已知人类苦味受体 TAS2R14 激动剂的分子特性被纳入药效团和形状基础模型中，并用于计算预测其他配体。通过转染 HEK293 细胞的 TAS2R14 钙成像来测试预测。虚拟筛选预测的体外测试成功率为 30-80%，发现 15 种临床药物可激活 TAS2R14。hERG 钾通道主要在心脏中表达，是苦味药物的常见脱靶。尽管已知 TAS2R14 配体具有巨大的化学多样性，但通过对计算预测的体外筛选，揭示了新型配体和药物以前未知的多效性。这为苦味信号调节的治疗适应症的传统和标准药物的合理再利用提供了可能。
