Structural Biology-Guided Design, Synthesis, and Biological Evaluation of Novel Insect Nicotinic Acetylcholine Receptor Orthosteric Modulators

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 underst...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2022-02, Vol.65 (3), p.2297-2312
Main Authors: Montgomery, Mark, Rendine, Stefano, Zimmer, Christoph T, Elias, Jan, Schaetzer, Jürgen, Pitterna, Thomas, Benfatti, Fides, Skaljac, Marisa, Bigot, Aurélien
Format: Article
Language:English
Subjects:
4-Butyrolactone - analogs & derivatives
4-Butyrolactone - chemistry
4-Butyrolactone - metabolism
Animals
Binding Sites
Coleoptera - drug effects
Coleoptera - metabolism
Crystallography, X-Ray
Drug Design
Humans
Insect Control - methods
Insect Proteins - chemistry
Insect Proteins - genetics
Insect Proteins - metabolism
Insecticides - chemical synthesis
Insecticides - metabolism
Insecticides - pharmacology
Molecular Conformation
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Pyridines - chemistry
Pyridines - metabolism
Pyrimidinones - chemistry
Pyrimidinones - metabolism
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - genetics
Receptors, Nicotinic - metabolism
Sulfur Compounds - chemistry
Sulfur Compounds - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01767