文献类型：期刊文献

英文题名：Identification of potential novel insect TRPV channel modulators by homology modeling, binding mode analysis, virtual screening studies and chemical optimization

作者：Li, Xiaoyang[1];Zhou, Cong[1];He, Lujue[1];Xu, Zhiping[1];Li, Zhong[1];Cheng, Jiagao[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China

年份：2024

卷号：48

期号：28

起止页码：12688

外文期刊名：NEW JOURNAL OF CHEMISTRY

收录：;EI(收录号：20242716645732);WOS:【SCI-EXPANDED(收录号:WOS:001259806300001)】；

基金：The authors gratefully acknowledge the financial support from the National Key Research and Development Program of China (2023YFD1700501), Natural Science Foundation of Shanghai (22ZR1415600), National Natural Science Foundation of China (22307039), China Postdoctoral Science Foundation (2023M731089), and Postdoctoral Fellowship Program of CPSF (GZC20230806).

语种：英文

外文关键词：Binding energy - Binding sites - Modulators - Pyridine - Scaffolds

摘要：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 revealed that pymetroizne formed T-shaped pi-pi interaction and H-bonds with the residues Phe688 on the S4 helix, as well as Glu627 on S2, and 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 a novel phenylhydrazidoyl scaffold, and the chemical optimization of this scaffold led to the discovery of compound B4 with 68.7% mortality rate against Aphis 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. A potential insect TRPV-targeted modulator was identified by virtual screening and chemical optimization.