The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood-brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

• Publication type
• Journal Article MeSH

The toxic effect of organophosphates is attributed to irreversible inhibition of acetylcholinesterase (AChE; EC 3.1.1.7), the enzyme that hydrolyses the neurotransmitter acetylcholine. Inhibition potency in vivo of one of the most toxic nerve agents--Russian VX (RVX;N,N-diethyl-2-[methyl-(2-methylpropoxy)phosphoryl]sulfanylethanamine) (1 x LD(50) dose administered intramuscularly, i.m.) was studied in rats. AChE in blood was inhibited by 50%, 3 min after i.m. RVX. Butylcholinesterase (BChE; EC 3.1.1.8) in plasma was inhibited less rapidly and only by 10-20%, 20 min after RVX. AChE and BChE activities in diaphragm were reduced only 35% and 15% at 30 min. While AChE and BChE activities were reduced only about 20% and 15%, respectively, the decline in activity was rapid, occurring within 3 min. These findings indicate that RVX most potently inhibits ChE outside the central nervous system.

• MeSH
• Acetylcholinesterase blood   MeSH
• Diaphragm drug effects   enzymology   MeSH
• Time Factors MeSH
• Behavior, Animal drug effects   MeSH
• Liver drug effects   enzymology   MeSH
• Rats MeSH
• Lethal Dose 50 MeSH
• Brain drug effects   enzymology   MeSH
• Organothiophosphorus Compounds toxicity   MeSH
• Rats, Wistar MeSH
• Tissue Distribution drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Organothiophosphorus Compounds MeSH
• S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate MeSH Browser