药效团
烟碱激动剂
化学
烟碱乙酰胆碱受体
乙酰胆碱受体
乙酰胆碱
合理设计
药理学
离子通道
受体
计算生物学
立体化学
生物化学
生物
遗传学
作者
Mark Montgomery,Stefano Rendine,Christoph Zimmer,Jan Eliáš,Jürgen Schaetzer,Thomas Pitterna,Fides Benfatti,Marisa Škaljac,Aurélien Bigot
标识
DOI:10.1021/acs.jmedchem.1c01767
摘要
The development of novel and safe insecticides remains an important need for a growing world population to protect crops and animal and human health. New chemotypes modulating the insect nicotinic acetylcholine receptors have been recently brought to the agricultural market, yet with limited understanding of their molecular interactions at their target receptor. Herein, we disclose the first crystal structures of these insecticides, namely, sulfoxaflor, flupyradifurone, triflumezopyrim, flupyrimin, and the experimental compound, dicloromezotiaz, in a double-mutated acetylcholine-binding protein which mimics the insect-ion-channel orthosteric site. Enabled by these findings, we discovered novel pharmacophores with a related mode of action, and we describe herein their design, synthesis, and biological evaluation.
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