Slight difference in the isomeric oximes K206 and K203 makes huge difference for the reactivation of organophosphorus-inhibited AChE: Theoretical and experimental aspects

Polisel, Daniel A.; Castro, Alexandre A. de; Mancini, Daiana T.; Cunha, Elaine F. F. da; França, Tanos C. C.; Ramalho, Teodorico C.

doi:10.1016/j.cbi.2019.05.037

Cited by 15 publications

(11 citation statements)

References 55 publications

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“…(%) Conc. According to the literature, the e ciency (reactivation percentage) of an oxime should be at least 10% to provide an appropriate remediation for the intoxicated patient [22,23]. In this regard, we observe different reactivation percentages through trimedoxime, taking into account its concentration as well as the type of OP-AChE complex.…”

Section: Systemmentioning

confidence: 73%

“…According to the coe cients of the equation, the importance of each stage for the AChE reactivation process by trimedoxime can be evaluated. Note that the highest modulus of the coe cient of the term ΔΔE # (relative activation energy) indicates that the reaction step presents a greater contribution for the AChE reactivation than the interaction energy [23,25].…”

Section: Investigating Kinetic Parameters For Biological Activity: Mementioning

confidence: 99%

“…The reactivation percentage (%) was calculated from the measured data according to the formula (Equation 2):The entire method is described in details in the work from Kuca and Cabal[29]. This same methodology was successfully employed in the work from Polisel et al (2019)[23].…”

mentioning

confidence: 99%

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

Castro

Polisel

Pereira

et al. 2020

Preprint

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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.

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Section: Systemmentioning

confidence: 73%

Section: Investigating Kinetic Parameters For Biological Activity: Mementioning

confidence: 99%

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

Castro

Polisel

Pereira

et al. 2020

Preprint

Self Cite

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“…Another study showed the influence of the non-nucleophilic end position on isomeric oximes, showing a large difference in the reactivation rate of each isomer in relation to AChE inhibited by different nerve agents [67]. The change in position of the carbamoyl group resulted in different reactivation percentages for different enzyme-nerve agent complexes.…”

Section: Ache Reactivation Processesmentioning

confidence: 99%

“…With the aid of theoretical studies, it was evidenced that the structural changes between the isomeric oximes resulted in different interactions with the cavity residues. In addition, one of the isomers' transition states was able to be better stabilized, especially in the cavity of the AChE-tabun cavity [67,68]. Diverse oximes-related aspects, such as interaction within AChE and reactivity, have been theoretically investigated [69].…”

Section: Ache Reactivation Processesmentioning

confidence: 99%

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

et al. 2020

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Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

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Advances Toward the Development of New Therapeutic Strategies Targeting Acetylcholinesterase and Its Remediation Processes

Castro

Assis

Gajo

et al. 2021

Functional Properties of Advanced Engineering Materials and Biomolecules

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Slight difference in the isomeric oximes K206 and K203 makes huge difference for the reactivation of organophosphorus-inhibited AChE: Theoretical and experimental aspects

Cited by 15 publications

References 55 publications

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

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

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

Advances Toward the Development of New Therapeutic Strategies Targeting Acetylcholinesterase and Its Remediation Processes

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