Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

Silva, Jorge Alberto Valle da; Pereira, Ander Francisco; LaPlante, Steven R.; Kuča, Kamil; Ramalho, Teodorico C.; França, Tanos C. C.

doi:10.3390/biom10020192

Cited by 13 publications

(8 citation statements)

References 38 publications

(77 reference statements)

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“…We were pleased to find that by selecting various docking techniques, such as free flexible docking, flexible docking with distance constraints, and covalent docking, we obtained promising results that allowed us to conduct a comprehensive analysis of OP–reactivator–cholinesterase interactions. Many groups involved in research on the reactivation of cholinesterases focus on an important stage in the reactivation process: the moment when the reactivator adopts a prereactivation pose [ 20 , 41 , 44 ]. Based on the reactivation cycle presented by Allgardsson et al [ 20 ] in which the reactivator can adopt nonreactivation or prereactivation conformations at the active site of OP-blocked cholinesterase, we performed an interaction analysis for five known reactivators modeling both states at AChE and BuChE active sites blocked by sarin or tabun.…”

Section: Discussionmentioning

confidence: 99%

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

et al. 2021

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Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.

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Section: Discussionmentioning

confidence: 99%

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

et al. 2021

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“…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 , 38 , 39 , 40 , 41 , 42 , 43 ]. The QM part of the calculations was performed through the Gaussian 09 package, at the DFT level and 6-31g(d,p) basis set [ 44 , 45 ].…”

Section: Methodsmentioning

confidence: 99%

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

Castro

Polisel

Pereira

et al. 2020

IJMS

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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.

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“…Treatments for general nerve agent and insecticide poisoning have utilized oxime derivatives as well. Reactivation of a VX-AChE complex using a deprotonated pralidoxime, or 2-pralidoxime (2-PAM), occurs through consecutive addition-elimination steps and shows promising results as an antidote [ 166 ]. Docking and QM/MM methods paired with experimental observations revealed that trimedoximes show potential to reactivate Mus musculus AChE, with the AChE-VX complex showing the best results [ 167 ], and MD simulations of 2-PAM with phosphorylated AChE support this claim [ 168 ].…”

Section: Inhibitionmentioning

confidence: 99%

A Comprehensive Review of Cholinesterase Modeling and Simulation

et al. 2021

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The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes.

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Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

Cited by 13 publications

References 38 publications

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

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

A Comprehensive Review of Cholinesterase Modeling and Simulation

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