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

Abstract

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 ...

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

“…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.…”

“…51 In our previous work, the molecular dynamic simulation of the access of oximes to the active site of AChE inhibited with tabun confirmed that the cationic oxime 2-PAM reaches the active site easily, while its anionic form is rejected. 41 Clearly, the anionic form of 2-PAM is formed inside the AChE active site. In that work, it was also shown that a neutral oxime analogue to 2-PAM, deazapralidoxime or 2-methylphenylaldoxime (16) can effectively access the active site of AChE, indicating that neutral oximes could function as inhibitors of AChE or potential reactivators of AChE inhibited by organophosphorus compounds, with potential to act in the human brain.…”

Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin

“…[2][3][4][5][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 …”

Organophosphorus compounds as chemical warfare agents: a review

“…38,44,45 Moreover, the distribution of charged residues in AChE results in a permanent dipole moment that is aligned with the axis of the active site gorge; this characteristic facilitates the attraction of a positively charged substrate, guiding it through the gorge. 46 The direct interaction of the substrate with the negatively charged residues situated in the gorge is shielded by the side chains of the aromatic residues. 47 This electrostatic steering caused by the huge dipole moment, associated with the quadrupole and other multipole moments of the enzyme, contributes to its high catalytic efficiency.…”