Computational insight on the binding and selectivity of target-subunit-dependent for neonicotinoid insecticides

The nicotinic acetylcholine receptor (nAChR), as an attractive target acted by neonicotinoid insecticides, was paid more and more attention in recent years. The mode of action study on neonicotinoids toward nAChR would present significant guidance on rational molecular design to further discover new insecticides. Four neonicotinoids including commercial agents imidacloprid and flupyradifurone, two previously synthesized compounds guadipyr and ethoxythiagua in our lab were docked into a putative model of aphid and honeybee nAChR, respectively, to explore the binding and selective mechanism of neonicotinoids in this study. The obtained results showed that a traditional H-bond interaction, as a dominating electrostatic driving force, always conferred the binding of four neonicotinoids not only to target aphid receptor but also to non-target honeybee one. Four neonicotinoids almost showed uniformly binding conformation into aphid receptor, namely, a vital electronegative nitro or butenolide group to be conserved to nestle in a non-selective β subunit. The bioassay study on Aphis gossypii also confirmed to be their excellent insecticidal activity with a lower LC50 value of 0.028–3.2 μg/mL. However, to non-target honeybee receptor, this special nitro or butenolide group of four neonicotinoids was no longer only binding to the non-selective β subunit of receptor. Three among four neonicotinoids like flupyradifurone, guadipyr and ethoxythiagua as a case of low bee-toxicity reported in the previous study, were happened to display an exactly inverted binding orientation, namely, an unusual electronegative group captured another selective α subunit. However, this high bee-toxicity imidacloprid remained one conserved conformation into the non-selective β subunit as that seen from aphid receptor. This unique molecular mechanism of selectively binding to honeybee receptor, particularly to different subunit, was proposed cautiously to be one of factor determined the distinctive bee-toxicity for four neonicotinoids. These findings on the diverse mode of action for neonicotinoids to target and non-target receptor would be helpful for on novel insecticides design with high bioactivity as well as good selectivity based on the structure of different insect nAChR.