Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects.

Alexandre De Castro,Eugenie Nepovimova,Daniel Polisel,Bruna Pereira,Elaine Da Cunha,Teodorico Ramalho,Kamil Kuca

doi:10.3390/ijms21186510

Abstract

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.

Highlights

Chemical weapons are defined as any chemical substance whose toxic properties are used for the purpose of killing, injuring or incapacitating an enemy in war or associated military operations [1,2,3]
Even with the efforts from world entities to ban the use of chemical weapons, under the Chemical Weapons Convention, diverse countries still have an arsenal of these chemical substances [4,5,6]
From the experimental assays with trimedoxime at lower concentrations, we can observe that the experimental values indicate a significant reactivation percentage for AChE–POX (50%), as well as a sufficient reactivation rate for AChE–Dichlorvos (DDVP) (17.3%)

Summary

Introduction

Chemical weapons are defined as any chemical substance whose toxic properties are used for the purpose of killing, injuring or incapacitating an enemy in war or associated military operations [1,2,3]. According to our experimental findings, 3 of 12 note that trimedoxime demonstrated the best results at higher concentrations (10−3 M) At this concentration, the oxime showed a remarkable reactivation percentage of 85.3% for AChE–VX reactivTaatbiolen..ARteaacctiovnacteionntraactitoivnityofof10tr−i3mMed, otrxiimmeed(odxaitma eobatlasioneedxhinibtirtisplaicagtoeoedxppeerrifmoremntaanl caessianyst)h.e reactivation of the AChE–sarin (GB) was more modestSfyosrteAmChE–Tabun (54%) (GA). An interesting outcome from this experimental investigation is the fact that trimedoxime does not reactivate the AChE–cyclosarin (GF) and AChE–soman (GD) adducts These trends are more deeply approached . From the experimental assays with trimedoxime at lower concentrations, we can observe that the experimental values indicate a significant reactivation percentage for AChE–POX (50%), as well as a sufficient reactivation rate for AChE–Dichlorvos (DDVP) (17.3%) This oxime showed insufficient reactivating power for the AChE inhibited by the other OP agents investigated, such as GA, GF and GD, considering a concentration of 10−5 M.

Docking Results

Investigating Kinetic Parameters for Biological Activity

Experimental Details

Docking Procedure

Conclusions