Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations.

Ya Gao, Yichi Zhang, Fengshou Wu, Jianfeng Pei, Xiaogang Luo, Xiulian Ju, Chunqing Zhao, Genyan Liu

Journal of agricultural and food chemistry 2020 Dec 16

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Broflanilide, a novel insecticide, is classified as a negative allosteric modulator (NAM) of insect γ-aminobutyric acid (GABA) receptors (GABARs) as desmethyl-broflanilide (DMBF) allosterically inhibits the GABA-induced responses. The G277M mutation of the Drosophila melanogaster GABAR subunit has been reported to abolish the inhibitory activity of DMBF. The binding mode of DMBF in insect GABARs needs to be clarified to understand the underlying mechanism of this mutation and to develop novel, efficient NAMs of insect GABARs. Here, we found that a hydrogen bond formed between DMBF and G277 of the D. melanogaster GABAR model might be the key interaction for the antagonism of DMBF by in silico simulations. The volume increase induced by the G277M mutation blocks the entrance of the binding pocket, making it difficult for DMBF to enter the binding pocket and thereby decreasing its activity. The following virtual screening and bioassay results identified a novel NAM candidate of insect GABARs. Overall, we reported a possible binding mode of DMBF in insect GABARs and proposed the insensitivity mechanism of the G277M mutant GABAR to DMBF using molecular simulations. The identified NAM candidates might provide more alternatives or potentials for the design of GABAR-targeting insecticides.

Citation

Ya Gao, Yichi Zhang, Fengshou Wu, Jianfeng Pei, Xiaogang Luo, Xiulian Ju, Chunqing Zhao, Genyan Liu. Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations. Journal of agricultural and food chemistry. 2020 Dec 16;68(50):14768-14780