title: Binding difference of fipronil with GABAARs in fruitfly and zebrafish: insights from homology modeling, docking, and molecular dynamics simulation studies.
abstract: Fipronil, which targets GABAA receptors (GABAARs), is the first phenylpyrazole insecticide widely used in crop protection and public hygiene. However, its high toxicity on fishes greatly limited its applications. In the present study, a series of computational methods including homology modeling, docking, and molecular dynamics simulation studies were integrated to explore the binding difference of fipronil with GABAARs from fruitfly and zebrafish systems. It was found that, in the zebrafish system, the H-bond between 6'Thr and fipronil exerted key effects on the recognition of fipronil, which was absent in the fruitfly system. On the other hand, in the fruitfly system, strong electrostatic interaction between 2'Ala and fipronil was favorable to the binding of fipronil but detrimental to the binding in the zebrafish system. These findings marked the binding difference of fipronil with different GABAARs, which might be helpful in designing selective insecticides against pests instead of fishes.
authors.affiliation: Shanghai Key Laboratory of Chemical Biology and ‡Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Jiagao
authors.initials: J
authors.lastname: Cheng
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Xusheng
authors.initials: X
authors.lastname: Shao
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xu
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Xu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004330:Drosophila / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D007306:Insecticides / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D007306:Insecticides; D011720:Pyrazoles; D011963:Receptors, GABA-A; D029961:Zebrafish Proteins; C082360:fipronil
keywords: GABAA receptors; docking; fipronil; homology modeling; molecular dynamics simulation