Computational Evidence for the Reactivation Process of Human Acetylcholinesterase Inhibited by Carbamates

Polisel

et al. 2020

IJMS

Self Cite

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.

Section: Methodsmentioning

confidence: 99%

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

Polisel

et al. 2020

IJMS

Self Cite

“…Thus, in this work, mixed quantum and molecular mechanics (QM/MM) combined with docking techniques were performed to determine the most likely reaction pathway for the OP degradation catalyzed by the wild-type DFPase. Actually, this theoretical strategy has been previously employed in other occasions [ 25 , 28 , 29 , 30 ], being intensively used in our current researches, and so, computational methods are necessary for allowing us to analyze them [ 10 ]. In an attempt to get more accurate results and electronic effects, QM calculations were carried out at the density functional theory (DFT) level with the Gaussian 09 package [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

Soares

et al. 2018

IJMS

Self Cite

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.

“…From these calculations, the energetic barrier of the reactivation process of each enzyme-OP complex with trimedoxime was determined. This theoretical strategy has been previously employed in other works [26,[39][40][41][42][43][44]. The QM part of the calculations was performed through the Gaussian 09 package, at the DFT level and 6-31g(d,p) basis set [45,46].…”

Section: Qm/mm Proceduresmentioning

confidence: 99%

Understand the interaction modes and reactivity of trimedoxime toward MmAChE inhibited by nerve agents: theoretical and experimental Aspects

Polisel

et al. 2020

Preprint

The organophosphorus compounds (OP) 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 greater spectrum of action in the 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 essays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences of interaction modes and reactivity of trimedoxime within AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most case, 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 was important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.