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Homology modeling of human α1β2γ2 and house fly β3 GABA receptor channels and Surflex-docking of fipronil

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Abstract

To further explore the mechanism of selective binding of the representative γ-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human α1β2γ2 and house fly β3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human α1β2γ2 and house fly β3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly β3 GABAR than with human α1β2γ2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human α1β2γ2 and house fly β3 GABARs may result in differential selectivity for fipronil.

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Acknowledgment

This study was supported by National Natural Science Foundation of China; contract/grant number: 20572084

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Authors and Affiliations

  1. School of Chemical Engineering & Pharmacy, Key Laboratory for Green Chemical Process of Ministry of Education, Wuhan Institute of Technology, Wuhan, 430073, People’s Republic of China

    Jin Cheng, Xiu-Lian Ju & Gen-Yan Liu

  2. School of Computer Science and Engineering, Wuhan Institute of Technology, Wuhan, 430073, People’s Republic of China

    Xiang-Yang Chen

Authors
  1. Jin Cheng
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  2. Xiu-Lian Ju
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  3. Xiang-Yang Chen
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  4. Gen-Yan Liu
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Correspondence to Xiu-Lian Ju.

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Cheng, J., Ju, XL., Chen, XY. et al. Homology modeling of human α1β2γ2 and house fly β3 GABA receptor channels and Surflex-docking of fipronil. J Mol Model 15, 1145–1153 (2009). https://doi.org/10.1007/s00894-009-0477-2

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  • DOI: https://doi.org/10.1007/s00894-009-0477-2

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