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.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, docking studies, molecular modeling, organophosphates, reactivation process, reactivators,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Phosphorus chemistry   MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Quantum Theory MeSH
• Humans MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Mice MeSH
• Organophosphates chemistry   MeSH
• Oximes chemistry   MeSH
• Protein Biosynthesis MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Sarin chemistry   MeSH
• Cluster Analysis MeSH
• Molecular Docking Simulation * MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Phosphorus MeSH
• Ligands MeSH
• Organophosphates MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH
• Sarin MeSH
• tabun MeSH Browser

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

• Keywords
• acetylcholinesterase, antidote, butyrylcholinesterase, organophosphate, oxime, paraoxon,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Antidotes chemical synthesis   pharmacology   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   MeSH
• Enzyme Assays MeSH
• Erythrocytes drug effects   enzymology   MeSH
• Insecticides antagonists & inhibitors   chemistry   toxicity   MeSH
• Protein Interaction Domains and Motifs MeSH
• Humans MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Oximes chemical synthesis   pharmacology   MeSH
• Paraoxon antagonists & inhibitors   chemistry   toxicity   MeSH
• Cholinesterase Reactivators chemical synthesis   pharmacology   MeSH
• Protein Structure, Secondary MeSH
• Molecular Docking Simulation MeSH
• Thermodynamics MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Insecticides MeSH
• Obidoxime Chloride MeSH
• Oximes MeSH
• Paraoxon MeSH
• Cholinesterase Reactivators MeSH

We have evaluated in vitro the potency of 23 oximes to reactivate human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) inhibited by racemic leptophos-oxon (O-[4-bromo-2,5-dichlorophenyl]-O-methyl phenyl-phosphonate), a toxic metabolite of the pesticide leptophos. Compounds were assayed in concentrations of 10 and 100 μM. In case of leptophos-oxon inhibited AChE, the best reactivation potency was achieved with methoxime, trimedoxime, obidoxime and oxime K027. The most potent reactivators of inhibited BChE were K033, obidoxime, K117, bis-3-PA, K075, K074 and K127. The reactivation efficacy of tested oximes was lower in case of leptophos-oxon inhibited BChE.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, leptophos-oxon, nerve agent, oxime, pesticide, reactivator, scavenger,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Erythrocytes drug effects   enzymology   MeSH
• Leptophos analogs & derivatives   chemistry   pharmacology   MeSH
• Humans MeSH
• Oximes chemistry   MeSH
• Pesticides chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Leptophos MeSH
• leptophos oxon MeSH Browser
• Oximes MeSH
• Pesticides MeSH