Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

• Klíčová slova
• acetylcholinesterase, mechanistic studies, nerve agents, realkylation, resurrection,
• MeSH
• acetylcholinesterasa * chemie   metabolismus   MeSH
• cholinesterasové inhibitory * chemie   farmakologie   MeSH
• indolochinony * chemie   MeSH
• kinetika MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa * MeSH
• cholinesterasové inhibitory * MeSH
• indolochinony * MeSH
• ligandy MeSH
• quinone methide MeSH Prohlížeč

The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found to be analogous to parent carboxamides (K027, K048 and K203). The inhibitory ability of thiocarboxamides was found in low µM levels for AChE and high µM levels for BChE. Their reactivation properties were screened on human recombinant AChE and BChE inhibited by nerve agent surrogates and paraoxon. One thiocarboxamide was able to effectively restore function of NEMP- and NEDPA-AChE, whereas two thiocarboxamides were able to reactivate BChE inhibited by all tested organophosphates. These results were confirmed by reactivation kinetics, where thiocarboxamides were proved to be effective, but less potent reactivators if compared to carboxamides.

• Klíčová slova
• Cholinesterase, inhibition, organophosphate, oxime, reactivation,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• organofosfáty chemická syntéza   chemie   farmakologie   MeSH
• oximy chemická syntéza   chemie   farmakologie   MeSH
• pyridinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• sulfhydrylové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• sulfhydrylové sloučeniny MeSH

Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

• Klíčová slova
• acetylcholinesterase, computational methods, mechanistic studies, nerve agents, reactivation, trimedoxime,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory metabolismus   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• nervová bojová látka chemie   MeSH
• organofosforové sloučeniny chemie   MeSH
• oximy chemie   MeSH
• reaktivátory cholinesterasy chemie   farmakologie   MeSH
• trimedoxim farmakologie   terapeutické užití   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• nervová bojová látka MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH
• trimedoxim MeSH