No abstract

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.

No abstract

Recent attacks on Syria using the nerve agent sarin warned once again the world and the scientists on the use of chemical weapons. It is known that nerve agents are potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine and, thus, transmitting of nerve impulses. The process of AChE inhibition by organophosphate (OP) can be reversed by a nucleophile, responsible for dephosphorylation of the residue Ser203 in the active site of the enzyme. In this sense, oximes exhibit this characteristic and are able to remove the neurotoxic and reactivate the enzyme. Here, we review experimental and theoretical results involving docking and quantum mechanical-molecular mechanics hybrid methods (QM/MM), using Molegro® and Spartan® softwares to analyze the interaction of different OPs and oximes with AChE and to evaluate kinetic constants of reactivation.Keywords: Chemical warfare; organophosphates; oximes; docking; QM/MM. ResumoOs ataques recentes na Síria utilizando o agente neurotóxico sarin alertaram mais uma vez a opinião pública mundial e a comunidade científica quanto à utilização de armas químicas. Sabe-se que agentes dos nervos são potentes inibidores da acetilcolinesterase (AChE), enzima responsável pela hidrólise do neurotransmissor acetilcolina e, consequentemente, pela transmissão de impulsos nervosos. A inibição da AChE por um organofosforado (OP) pode ser revertida por um nucleófilo, que desfosforila a Ser203 no sítio ativo da enzima. Nesse sentido, as oximas têm essa característica, pois são capazes de remover o neurotóxico e reativar a enzima. Neste trabalho, revisamos alguns resultados experimentais e teóricos que envolvem estudos de ancoramento molecular e métodos híbrídos quanto-mecânicos/mecânica molecular (QM/MM) usando os softwares Molegro® e Spartan® para analisar as interações de diferentes oximas e OPs com a AChE e avaliar as constantes cinéticas de reativação.Palavras-chave: Guerra química; organofosforados; oximas; ancoramento; QM/MM.

It is known that nerve agents are potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine and, thus, transmission of nerve impulses. The process of AChE inhibition by nerve agents can be reversed by a nucleophile able to dephosphorylate the enzyme. In this sense, oximes exhibit this characteristic and are able to remove the neurotoxic and reactivate AChE. Here, we review experimental and theoretical results involving docking and quantum mechanical-molecular mechanics hybrid methods (QM/MM), using Molegro ® and Spartan ® softwares to analyze the interaction of different nerve agents and oximes with AChE and to evaluate kinetic constants of reactivation.