Theoretical assessment of the performances of commercial oximes on the reactivation of acetylcholinesterase inhibited by the nerve agent A-242 (novichok)
Language English Country Great Britain, England Media print-electronic
Document type Journal Article
PubMed
35489467
DOI
10.1016/j.fct.2022.113084
PII: S0278-6915(22)00282-4
Knihovny.cz E-resources
- Keywords
- A-242, A-series nerve agents, Commercial oximes, Near-attack conformation,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes pharmacology MeSH
- Cholinesterase Inhibitors chemistry toxicity MeSH
- Humans MeSH
- Nerve Agents * toxicity MeSH
- Organophosphates MeSH
- Oximes chemistry pharmacology MeSH
- Pyridinium Compounds pharmacology MeSH
- Cholinesterase Reactivators * pharmacology MeSH
- Molecular Docking Simulation MeSH
- Trimedoxime pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Cholinesterase Inhibitors MeSH
- Nerve Agents * MeSH
- novichok MeSH Browser
- Organophosphates MeSH
- Oximes MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators * MeSH
- Trimedoxime MeSH
The nerve agents of the A-series are relatively recent chemical weapons with no antidote available yet. Once inside the human body, those chemicals act similarly to the classic nerve agents, by binding to the catalytic residue Serine 203 (Ser203) of human acetylcholinesterase (HssAChE) and thus preventing the proper function of this enzyme. However, there is no experimental evidence yet if the current antidotes for intoxication by nerve agents are also capable of restoring AChE inhibited by the nerve agents of the A-series. In order to launch some light on this issue, we used computational techniques (molecular docking, molecular dynamics and MM-PBSA interaction energy calculations) to assess the performances of the four currently available commercial oximes (2-PAM, HI-6, obidoxime and trimedoxime) when in contact with HssAChE inhibited by the agent A-242. Based on the near-attack conformation (NAC) criterion, our results suggest that the commercial oximes would have limited efficacy to reactivate the enzyme since they are not able to properly approach the adduct Ser203-A-242. Among those oximes, trimedoxime seems to be the most promising, since it showed lower values of energy in the MM-PBSA calculations, a higher stability inside the catalytic anionic center (CAS) of HssAChE, and was able to adopt a position closer to the NAC that could enable the reactivation mechanism.
References provided by Crossref.org
A-agents, misleadingly known as "Novichoks": a narrative review