Karaman Rafik, Nowak Stefanie, Di Pizio Antonella, Kitaneh Hothaifa, Abu-Jaish Alaa, Meyerhof Wolfgang, Niv Masha Y, Behrens Maik
Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel.
Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
Chem Biol Drug Des. 2016 Jul;88(1):66-75. doi: 10.1111/cbdd.12734. Epub 2016 Feb 17.
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.
在口腔中感知潜在有害的苦味物质是由一组约25种受体实现的，这些受体被称为TAS2R，它们在专门的感觉细胞中表达，并识别各自但有重叠的苦味化合物组。这些受体的调谐宽度不同，从窄调谐受体到宽调谐受体。人类最宽泛调谐的苦味受体之一是TAS2R14，它能识别种类繁多、化学性质各异的合成和天然苦味化合物，包括许多药物。这表明该受体拥有一个大的、易于接近的配体结合口袋。为了探究配体结合口袋的可及性和大小，我们对同源激动剂进行化学修饰，并在功能测定中测试受体反应。通常可以在不消除激动活性的情况下向激动剂添加大的官能团。新合成的激动剂衍生物在受体的结合位点进行建模，以便与母体物质进行比较，并对该系列化合物的体外活性进行合理化分析。
