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