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

Int J Mol Sci. 2020 Sep 5;21(18):6510. 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.

Keywords: acetylcholinesterase; computational methods; mechanistic studies; nerve agents; reactivation; trimedoxime.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Antidotes / pharmacology
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Reactivators / chemistry*
  • Cholinesterase Reactivators / pharmacology
  • Computational Biology / methods
  • Humans
  • Mice
  • Nerve Agents / chemistry
  • Organophosphorus Compounds / chemistry
  • Oximes / chemistry
  • Rats
  • Trimedoxime / pharmacology*
  • Trimedoxime / therapeutic use*

Substances

  • Antidotes
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Nerve Agents
  • Organophosphorus Compounds
  • Oximes
  • Trimedoxime
  • Acetylcholinesterase