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 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.