Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations
| Autor: | Elaine F. F. da Cunha, Daiana T. Mancini, Teodorico C. Ramalho, Alexandre A. de Castro, Melissa S. Caetano, Flávia V. Soares, Daniela Rodrigues Silva, Ander Francisco Pereira, Telles Cardoso Silva |
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| Rok vydání: | 2019 |
| Předmět: |
Sarin
Stereochemistry 030303 biophysics Molecular mechanics QM/MM 03 medical and health sciences chemistry.chemical_compound Organophosphorus Compounds Structural Biology Catalytic Domain medicine Humans Pyrophosphatases Molecular Biology Diisopropyl-fluorophosphatase Nerve agent chemistry.chemical_classification Principal Component Analysis 0303 health sciences Hydrogen Bonding Organothiophosphorus Compounds General Medicine Acetylcholinesterase Molecular Docking Simulation Biodegradation Environmental Enzyme chemistry Quantum Theory Enantiomer Nerve Agents medicine.drug |
| Zdroj: | Journal of Biomolecular Structure and Dynamics. 37:2154-2164 |
| ISSN: | 1538-0254 0739-1102 |
| Popis: | Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma. |
| Databáze: | OpenAIRE |
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