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Asymmetric biocatalysis of the nerve agent VX by human serum paraoxonase 1: molecular docking and reaction mechanism calculations

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Abstract

Organophosphorus compounds have been employed in agricultural activity for a long time, causing serious public health problems. Due to their toxic properties, these compounds have also been used as chemical weapons. In view of this scenario, the catalytic degradation and the development of bioremediation processes of organophosphorus compounds have been of wide interest. Among several enzymes capable of degrading organophosphorus compounds, the human serum paraoxonase 1 has shown good potential for this purpose. To evaluate the interaction mode between the human serum paraoxonase 1 (wild-type and mutants) enzymes and the VX compound, one of the most toxic organophosphorus compounds known, molecular docking calculations were conducted. In addition, seeking to analyze the reaction pathway and the stereochemistry preference by human serum paraoxonase 1 and the R p and S p enantiomers of VX, quantum mechanical/molecular mechanics calculations were performed. Our theoretical findings put in evidence that the wild-type and mutant human serum paraoxonase 1 enzymes strongly interact with VX. Moreover, with the quantum mechanical/molecular mechanics study, we observed that the human serum paraoxonase 1 preferentially degrades one enantiomer in relation to the other. The current results indicate key points for designing new, more efficient mutant human serum paraoxonase 1 enzymes for VX degradation.

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Acknowledgements

The authors wish to thank the Brazilian financial agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo ao Ensino e Pesquisa de Minas Gerais (FAPEMIG) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ Ministério da Defesa (CAPES/MD) for financial support, and the Federal University of Lavras (UFLA) for providing the physical infrastructure and working space. This work was supported by Excellence project FIM UHK.

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Authors and Affiliations

  1. Laboratory of Molecular Modeling, Chemistry Department, Federal University of Lavras, Lavras, MG, 37200-000, Brazil

    Jaqueline Sartorelli, Alexandre A. de Castro, Teodorico C. Ramalho, Juliana O. S. Giacoppo, Daiana T. Mancini & Elaine F. F. da Cunha

  2. Center for Basic and Applied Research, University of Hradec Kralove, Hradec, Kralove, Czech Republic

    Teodorico C. Ramalho

  3. Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, MG, 35400-000, Brazil

    Melissa S. Caetano

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  1. Jaqueline Sartorelli
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  2. Alexandre A. de Castro
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  3. Teodorico C. Ramalho
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  4. Juliana O. S. Giacoppo
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  6. Melissa S. Caetano
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  7. Elaine F. F. da Cunha
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Correspondence to Teodorico C. Ramalho.

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Teodorico C. Ramalho and Elaine F. F. da Cunha contributed equally to this work.

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Sartorelli, J., de Castro, A.A., Ramalho, T.C. et al. Asymmetric biocatalysis of the nerve agent VX by human serum paraoxonase 1: molecular docking and reaction mechanism calculations. Med Chem Res 25, 2521–2533 (2016). https://doi.org/10.1007/s00044-016-1704-x

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