Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin

Abstract

No presente trabalho foi aplicada uma metodologia teórica desenvolvida em um trabalho anterior que utiliza os programas Molegro ® e Spartan ® para avaliar as constantes cinéticas de associação e reativação de oximas, em relação a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlação entre as energias livres teóricas de ligação das oximas e os dados experimentais, corroborando a metodologia como adequada para a predição de parâmetros cinéticos e termodinâmicos, os quais podem ser úteis para o planejamento e seleção de novas e mais efetivas oximas.In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes. Keywords: acetylcholinesterase, QM/MM, chemical mechanism of reactivation, neurotoxic agents IntroductionThe action of the nerve agents 1,2 as inhibitors of the enzyme acetylcholinesterase (AChE) stops the hydrolysis of the neurotransmitter acetylcholine and can lead to an irreversible inhibition of this enzyme (aging) thus triggering the cholinergic syndrome.3 To avoid this it's necessary a nucleophile, like an oxime, whose hydroxyl group is believed to be able to remove the nerve agent from the active site and reactivate AChE (Scheme 1). This reactivation reaction (illustrated in equation 1) involves, first, the association of the oxime to the inhibited enzyme (EIOx) and then the reactivation of the enzyme by the leaving of the oxime complexed to the neurotoxic agent (I-Ox).Where K R and k r are the dissociation constants, which represent the affinity of oximes for the inhibited AChE, and the rate constant for the decomposition of the stable enzyme-inhibitor-reactivator complex, respectively. 4,5The literature reports many structurally different oximes able to perform the reactivation of AChE inhibited by several different nerve agents, but one structure able to act efficiently against all the existing neurotoxic agents has not yet been reported 4,5 and oximes that are efficient against one specific nerve agent can be completely ineffective with another.2-6 Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 we have Methodology Ligands data set and docking energy calculationsThe in vitro data of K R and k r for the oximes studied in this work (Figure 1) regarding AChE inhibited by cyclosarin, were reported by Kassa et al. 5 Crystallogr...

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“…Os sintomas são angústia, perda da coordenação e convulsões que levam à morte. 23 Atualmente, o tratamento padrão contra o envenenamento por OP inclui a utilização de um anticolinérgico, normalmente atropina intravenosa, para diminuir os efeitos da acumulação da ACh, combinada com um depressor do sistema nervoso central, como o diazepam, para reduzir convulsões e espasmos, e uma oxima catiônica para reativar a AChE. Esses três componentes são combinados em seringas autoinjetoras que podem ser levadas para o campo de batalha.…”

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