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Structural determinants of imidacloprid-based nicotinic acetylcholine receptor inhibitors identified using 3D-QSAR, docking and molecular dynamics

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Abstract

Nicotinic acetylcholine receptor (nAChR) is a target for insect-selective neonicotinoid insecticides (NNs), exemplified by imidacloprid (IMI). In the present study, 78 IMI derivatives reported as inhibitors of Drosophila melanogaster nAChR (Dm-nAChR) and Musca domestica nAChR (Md-nAChR) were used for three-dimensional quantitative structure–activity relationship (3D-QSAR) studies. Two optimal models with good predictive power were obtained: Q 2 = 0.64, R 2 pred = 0.72 for Dm-nAChR, and Q 2 = 0.63, R 2 pred = 0.62 for Md-nAChR. In addition, homology modeling, molecular dynamic (MD) simulation, and molecular docking also showed that amino acids located within loops A, C, D and E play key roles in the interaction of Dm-/Md-nAChR with NNs. This is highly consistent with the results of graphical analysis of 3D-QSAR contour plots. Mutation analysis also implicates the Y/S mutation within loop B as being associated closely with NN resistance in Drosophila and Musca. The results obtained lead to a better understanding not only of interactions between these antagonists and Dm-/Md-nAChR, but also of the essential features that should be considered when designing novel inhibitors with desired activities.

Left panel Structure of imidacloprid (IMI)—an insect-selective neonicotinoid insecticide (NN). Right panel IMI interaction with Drosophila/Musca nicotinic acetylcholine receptor (nAChR)

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Acknowledgments

This work is supported by the high-performance computing platform of northwest A & F University. The research is supported financially by the Fund of northwest A & F University. The authors are grateful to Prof. L. Yang for access to Sybyl software.

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Authors and Affiliations

  1. College of Veterinary Medicine, Northwest A & F University, Yangling, 712100, Shaanxi, China

    Qinfan Li, Xiangya Kong & Lihui Zhang

  2. College of Life Science, Northwest A & F University, Yangling, 712100, Shaanxi, China

    Zhengtao Xiao, Fangfang Wang, Hong Zhang & Yonghua Wang

  3. Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, 116023, Liaoning, China

    Yan Li

  4. Center of Bioinformatics, Northwest A & F University, Yangling, 712100, Shaanxi, China

    Yonghua Wang

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  1. Qinfan Li
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  2. Xiangya Kong
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  3. Zhengtao Xiao
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  4. Lihui Zhang
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  5. Fangfang Wang
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  6. Hong Zhang
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  7. Yan Li
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  8. Yonghua Wang
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Correspondence to Yonghua Wang.

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Qinfan Li and Xiangya Kong contribute equally

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Li, Q., Kong, X., Xiao, Z. et al. Structural determinants of imidacloprid-based nicotinic acetylcholine receptor inhibitors identified using 3D-QSAR, docking and molecular dynamics. J Mol Model 18, 2279–2289 (2012). https://doi.org/10.1007/s00894-011-1293-z

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  • DOI: https://doi.org/10.1007/s00894-011-1293-z

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