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

International Journal of Molecular Sciences

卷:21

Kamil Kuca¹  Eugenie Nepovimova²  BrunaT. L. Pereira³  ElaineF. F. da Cunha³  TeodoricoC. Ramalho³  DanielA. Polisel³  AlexandreA. de Castro³ 

[1] Biomedical Research Center, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic;

[2] Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03 Hradec Kralove, Czech Republic;

[3] Department of Chemistry, Federal University of Lavras, 37200-000 Lavras, Brazil;

关键词: nerve agents;    acetylcholinesterase;    trimedoxime;    reactivation;    mechanistic studies;    computational methods;   

DOI  :  10.3390/ijms21186510

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown