CNRS, Univ. Grenoble Alpes, CEA, IBS, 38000 Grenoble, France.
Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Tianjin 300071, People's Republic of China.
Structure. 2020 Oct 6;28(10):1131-1140.e4. doi: 10.1016/j.str.2020.07.004. Epub 2020 Jul 28.
Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.
止吐药常被误解为利基药物，却是癌症治疗的关键要素，可缓解化疗最令人恐惧的副作用。5-羟色胺 5-HT3 受体拮抗剂是最常被开处用于控制化疗引起的恶心和呕吐的药物。自 20 世纪 80 年代以来，这些拮抗剂一直是临床成功的药物，但由于难以获得药物-受体复合物的结构，我们对它们在分子水平上如何运作的理解一直受到阻碍。在这里，我们报告了与帕洛诺司琼结合的 5-HT3 受体的冷冻电镜结构。我们使用分子动力学研究了帕洛诺司琼、格拉司琼、多拉司琼、昂丹司琼和盐酸兰地司琼的结合情况，涵盖了临床上使用的整套拮抗剂。结构和计算结果提供了药物结合模式的详细原子见解。根据我们的数据，我们建立了一个全面的框架，阐述了 -setron 药物家族的抑制机制。
