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Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18450%2F17%3A50005092" target="_blank" >RIV/62690094:18450/17:50005092 - isvavai.cz</a>

  • Výsledek na webu

    <a href="http://dx.doi.org/10.1080/07391102.2016.1178173" target="_blank" >http://dx.doi.org/10.1080/07391102.2016.1178173</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1080/07391102.2016.1178173" target="_blank" >10.1080/07391102.2016.1178173</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin

  • Popis výsledku v původním jazyce

    Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

  • Název v anglickém jazyce

    Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin

  • Popis výsledku anglicky

    Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10609 - Biochemical research methods

Návaznosti výsledku

  • Projekt

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2017

  • Kód důvěrnosti údajů

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

Údaje specifické pro druh výsledku

  • Název periodika

    Journal of biomolecular structure and dynamics

  • ISSN

    0739-1102

  • e-ISSN

  • Svazek periodika

    35

  • Číslo periodika v rámci svazku

    6

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    11

  • Strana od-do

    1272-1282

  • Kód UT WoS článku

    000400177700009

  • EID výsledku v databázi Scopus

    2-s2.0-84976303066