RT Journal Article
SR Electronic
T1 The binding of palonosetron and other antiemetic drugs to the serotonin 5-HT3 receptor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.14.947937
DO 10.1101/2020.02.14.947937
A1 Eleftherios Zarkadas
A1 Hong Zhang
A1 Wensheng Cai
A1 Gregory Effantin
A1 Jonathan Perot
A1 Jacques Neyton
A1 Christophe Chipot
A1 Guy Schoehn
A1 Francois Dehez
A1 Hugues Nury
YR 2020
UL http://biorxiv.org/content/early/2020/02/15/2020.02.14.947937.abstract
AB 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 (CINV). 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 cryo-EM 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 the 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.