Asymmetric biocatalysis of the nerve agent VX by human serum paraoxonase 1: molecular docking and reaction mechanism calculations
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- 作者：Jaqueline Sartorelli ; Alexandre A. de Castro…
- 关键词：Molecular ; docking ; HuPON1 ; VX ; QM/MM ; Mutation ; Homology modeling
- 刊名：Medicinal Chemistry Research
- 出版年：2016
- 出版时间：November 2016
- 年：2016
- 卷：25
- 期：11
- 页码：2521-2533
- 全文大小：1,669 KB
- 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
- 出版者：Springer US
- ISSN：1554-8120
- 卷排序：25
文摘
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 Rp and Sp 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.