Molecular structure, conformational analysis and charge distribution of pralidoxime: Ab initio and DFT studies

Reativadores eficientes de Aceticolinesterase são fundamentais para o desenvolvimento de antídotos contra o envenenamento por pesticidas neurotóxicos e agentes de guerra química. Todavia, o mecanismo da reação de reativação e as características estruturais dos reativadores conhecidos são pouco compreendidos. Com o objetivo de estudar o comportamento dinâmico e o efeito da carga líquida do antídoto na reativação desta enzima, foi conduzido um estudo por dinâmica molecular da acetilcolinesterase humana inibida por tabun em complexo com o antídoto pralidoxima e com seu análogo deazapralidoxima nas formas neutra e aniônica. Os resultados mostraram que a carga positiva da pralidoxima é importrante para sua admissão e permanência dentro do sítio ativo. Além disso, os análogos, diferente da pralidoxima, quando colocados dentro do sítio ativo, se distanciam do resíduo serina fosforilado da enzima e são repelidos pelo potencial eletrostático na entrada do canal que conduz ao sítio ativo.Efficient acetylcholinesterase reactivators are fundamental for the development of antidotes against poisoning by neurotoxic pesticides and chemical warfare agents. However, the mechanism of the reactivation reaction and the structural characteristics of the known reactivators are poorly understood. In order to study the dynamic behavior and the effect of the antidote net charge in the reactivation of this enzyme, we carried out a molecular dynamics study of human acetylcholinesterase inhibited by tabun in complex with the antidote pralidoxime and with its deaza analogues in the neutral and anionic forms. Results show that the positive charge of pralidoxime is important for its admission and permanence inside the active site. Also, the analogues, unlike pralidoxime, when forced inside the active site, move away from the phosphorilated serine residue of the enzyme and are repelled by the electrostatic potential at the entrance of the channel that conducts to the active site. Keywords: acetylcholinesterase, molecular dynamics, tabun, antidotes, neurotoxic agents IntroductionThe intensive use of neurotoxic organophosphorous compounds as pesticides in agriculture, as well as their potential use as mass destruction agents in chemical warfare, has attracted attention to the development of efficient antidotes for this type of poisoning.1,2 However, the knowledge on the appropriate treatment for patients exposed to this kind of compounds is limited to few groups of physicians around the world. 1,2One particularly important family of lethal tactical warfare chemicals is the group known as the nerve agents, which are closely related in chemical structure and biological action to many commonly used organophosphorous insecticides, but which are much more lethal. 1,2The nerve agents are esters of phosphoric acid and are potent inhibitors of acetylcholinesterase, a fundamental enzyme for ending nervous impulses. These compounds inhibit all acetylcholinesterases, including the human enzyme (HuAChE), by phosphorylating a serine hydroxyl group (Ser203 in ...

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular dynamics of the interaction of pralidoxime and deazapralidoxime with acetylcholinesterase inhibited by the neurotoxic agent tabun

Gonçalves¹,

França²,

Wilter³

et al. 2006

“…10 The most effective reported reactivation compounds are cationic oximes prepared from pyridine aldehydes. As shown in Figure 3, 1,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] when they are converted to their conjugated bases, oximes are believed to function as nucleophiles. In this example, pralidoxime (2-PAM, 13) is converted to the anionic form (14), which makes a nucleophilic attack on the phosphate group, forming the phosphorylated oxime (15) and releasing the activity of AChE.…”

Section: Introductionmentioning

confidence: 99%

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Ribeiro¹,

Prates²,

Alves³

et al. 2012

Importantes agentes para defesa contra armas de guerra química são reativadores da acetilcolinesterase humana (huAChE) inibida por compostos organofosforados neurotóxicos (OP), e precisam de uma permeabilidade razoável pela barreira hematoencefálica (HB). Neste trabalho, oximas neutras, que penetram HB melhor do que as oximas catiônicas atualmente utilizadas como agentes de defesa, foram testadas como reativadores da huAChE inibida com paraoxon usando o método de Ellman modificado e pralidoxima (2-PAM) como padrão positivo. A oxima neutra mais ativa foi a 2-tiofenoaldoxima, que reativou 93% da huAChE inibida, sendo 12% mais eficiente do que a 2-PAM. Os resultados mostraram que oximas neutras simples possuem potencial para atuarem como antídotos para intoxicação com OPs neurotóxicos, sugerindo maior investigação no desenvolvimento de agentes de defesa neutros.Important defense agents against chemical warfare weapons, which are reactivators of human acetylcholinesterase (huAChE) inhibited by neurotoxic organophosphorus compounds (OP), need a reasonable permeation of the hematoencephalic barrier (HB). In this work, neutral oximes, which permeate HB better than the cationic oximes currently used as defense agents, were tested as reactivators of huAChE inhibited with paraoxon using the modified Ellman test with pralidoxime (2-PAM) as positive standard. The most active neutral oxime was (thiophen-2-yl)aldoxime, which reactivated 93% of the inhibited huAChE and was 12% more effective than 2-PAM. The results showed that simple neutral oximes have potential to function as antidotes for intoxication with neurotoxic OPs, suggesting further research on the development of neutral defense agents.Keywords: neutral oximes, huAChE reactivation, paraoxon, chemical warfare, (thiophen-2-yl)aldoxime IntroductionIntoxication with neurotoxic organophosphorus compounds is a serious problem caused by some pesticides used in agriculture, such as paraoxon (1) and malathion (2) ( Figure 1) and chemical warfare agents. [1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) ( Figure 1). Though their use is prohibited by the United Nations, these agents have been employed as weapons by terrorist groups and by countries that did not sign the Chemical Weapon Convention administered by the Organization for the Prohibition of Chemical Weapons (OPCW).The principal target for the action of neurotoxic organophosphorus compounds is the enzyme acetylcholinesterase (AChE), a serine hydrolase that controls the nerve impulses at the cholinergic receptors in the central and peripheral nervous systems. 1,15-20 As shown in Ribeiro et al. 1217 Vol. 23, No. 7, 2012 Figure 2, the function of AChE (7) is the hydrolysis of the nerve impulse transmitter acetylcholine...

“…Usually, it is considered that the oxime reacts in the deprotonated form (oximate) in nucleophilic reactivation, as represented in Figure 14. 147 However, there are indications pointing to the possibility that the reaction occurs with the neutral oxime, instead of the oximate; 148 additional studies are needed to elucidate this question. 149 The nucleophilic attack of the oximate (or oxime) to the phosphorus atom is facilitated by the polarization of the phosphoryl bond, which is enhanced by the oxyanion hole.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

231

178

Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.