In silico study on the influence of isomeric oximes for reactivation of Organophosphorus-inhibited AChE

Abstract

Organophosphorus compounds (OP) have been used as chemical weapons since the 1930s by the Germans, when researching new pesticides. These compounds have the ability to i nhibit the enzyme Acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of the neurotransmitter Acetylcholine. With inhibition, neurotransmitter accumulation occurs at nerve endings, resulting in a cholinergic crisis, which can lead to death. Several substances have been studied in order to reactivate the catalytic activity of AChE, among them the oximes. Oximes are a class of compounds which, through a attack of one extremity (oxime group) to the phosphorus atom of the inhibitor, have shown good results in the reactivation process of inhibited-AChE. So far, there is no universal reactivator and small structural changes in oximes result in different experimental outcomes. Therefore, the objective of this study is to compare two isomeric oximes, K203 and K206, whose difference is the position of the carbamoyl group in the pyridinium ring (positions 4 and 3 for K203 and K206, respectively). For this, theoretical molecular docking calculations and QM/MM calculations of reaction mechanism were performed. The results showed that the slight difference between the oximes generate different reactivation rates in relation to the different inhibitors studied, as well, as significantly influence on intermolecular interaction energy and on activation barrier energy in relation to AChE inhibited by different nerve agents.