Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18450%2F16%3A50004719" target="_blank" >RIV/62690094:18450/16:50004719 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.2174/1386207319666160325113844" target="_blank" >http://dx.doi.org/10.2174/1386207319666160325113844</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2174/1386207319666160325113844" target="_blank" >10.2174/1386207319666160325113844</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase

Popis výsledku v původním jazyce

During World War II, organophosphorus compounds with neurotoxic action were developed and used as the basis for the development of structures currently used as pesticides in the agricultural industry. Among the nerve agents, Tabun, Sarin, Soman and VX are the most important. The factor responsible for the high toxicity of organophosphorus (OP) is the acetylcholinesterase inhibition. However, one of the characterized enzymes capable of degrading OP is Phosphotriesterase (PTE). This enzyme has generated considerable interest for applications of rapid and complete detoxification. Due to the importance of bioremediation methods for the poisoning caused by OP, this work aims to study the interaction mode between the PTE enzyme and organophosphorus compounds, in this case, Sarin, Soman, Tabun and VX have been used, which are potent acetylcholinesterase inhibitors, taking into account the enantiomers &quot;Rp&quot; and &quot; Sp&quot; of each compound, with the Sp-enantiomers presenting the higher toxicity. With that, we were able to demonstrate the existence of the stereochemical preference by PTE in these compounds. With the purpose of increasing the speed of the hydrolysis mechanism, we have proposed a modification in the enzyme active site structure, where Zn2+ ions were substituted by Al3+ ions. To analyze the stability of Al3+ ions in the wild-type PTE active site, MD simulations were also performed. This mutation brought relevant results; in this case, there was a reduction of the reaction energy barrier for all the compounds, mainly for VX in which the reaction presented lower activation energy values, and consequently, a faster hydrolysis process.

Název v anglickém jazyce

Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase

Popis výsledku anglicky

During World War II, organophosphorus compounds with neurotoxic action were developed and used as the basis for the development of structures currently used as pesticides in the agricultural industry. Among the nerve agents, Tabun, Sarin, Soman and VX are the most important. The factor responsible for the high toxicity of organophosphorus (OP) is the acetylcholinesterase inhibition. However, one of the characterized enzymes capable of degrading OP is Phosphotriesterase (PTE). This enzyme has generated considerable interest for applications of rapid and complete detoxification. Due to the importance of bioremediation methods for the poisoning caused by OP, this work aims to study the interaction mode between the PTE enzyme and organophosphorus compounds, in this case, Sarin, Soman, Tabun and VX have been used, which are potent acetylcholinesterase inhibitors, taking into account the enantiomers &quot;Rp&quot; and &quot; Sp&quot; of each compound, with the Sp-enantiomers presenting the higher toxicity. With that, we were able to demonstrate the existence of the stereochemical preference by PTE in these compounds. With the purpose of increasing the speed of the hydrolysis mechanism, we have proposed a modification in the enzyme active site structure, where Zn2+ ions were substituted by Al3+ ions. To analyze the stability of Al3+ ions in the wild-type PTE active site, MD simulations were also performed. This mutation brought relevant results; in this case, there was a reduction of the reaction energy barrier for all the compounds, mainly for VX in which the reaction presented lower activation energy values, and consequently, a faster hydrolysis process.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10609 - Biochemical research methods

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Combinatorial chemistry and high throughput screening

ISSN

1386-2073

e-ISSN

—

Svazek periodika

19

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

AE - Spojené arabské emiráty

Počet stran výsledku

11

Strana od-do

334-344

Kód UT WoS článku

000378053300010

EID výsledku v databázi Scopus

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