Insect transient receptor potential vanilloid (TRPV) channels serve as important targets for pyridine azomethine insecticides, playing crucial roles in sustainable pest management. In this study, the homology model of Nilaparvata lugens TRPV, a heterotetramer comprising the Nanchung and Inactive subunits, was constructed using the crystal structures of rabbit TRPV5 and human TRPV6 as templates. The potential binding site and binding modes between pyridine azomethine insecticides and N. lugens TRPV were further investigated. Our findings reveled that pymetroizne formed T-shaped π-π interaction and H-bonds with the residues Phe688 on S4 helix, as well as Glu627 on S2, Ala643 and Arg646 on S3 of the Nanchung subunit, respectively. A hierarchical virtual screening protocol was then used to identify a potential insect TRPV channel modulator A6 with novel phenylhydrazidoyl scaffold, and the chemical optimization of this scaffold led to the discovery of compound B4 with 68.7% mortality rate against A. craccivora at 200.0 mg•L-1.These findings lay a foundation not only for exploring the mechanisms of action of pymetrozine but also for developing new insecticides targeting the TRPV channels of pests.

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