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.

• Klíčová slova
• acetylcholinesterase, butyrylcholinesterase, docking studies, molecular modeling, organophosphates, reactivation process, reactivators,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• fosfor chemie   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• kvantová teorie MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• myši MeSH
• organofosfáty chemie   MeSH
• oximy chemie   MeSH
• proteosyntéza MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin chemie   MeSH
• shluková analýza MeSH
• simulace molekulového dockingu * MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• fosfor MeSH
• ligandy MeSH
• organofosfáty MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH
• sarin MeSH
• tabun MeSH Prohlížeč

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.

• Klíčová slova
• acetylcholinesterase, antidote, butyrylcholinesterase, organophosphate, oxime, paraoxon,
• MeSH
• acetylcholinesterasa chemie   MeSH
• antidota chemická syntéza   farmakologie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• enzymatické testy MeSH
• erytrocyty účinky léků   enzymologie   MeSH
• insekticidy antagonisté a inhibitory   chemie   toxicita   MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• oximy chemická syntéza   farmakologie   MeSH
• paraoxon antagonisté a inhibitory   chemie   toxicita   MeSH
• reaktivátory cholinesterasy chemická syntéza   farmakologie   MeSH
• sekundární struktura proteinů MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• insekticidy MeSH
• obidoxim chlorid MeSH
• oximy MeSH
• paraoxon MeSH
• reaktivátory cholinesterasy 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.

• Klíčová slova
• acetylcholinesterase, butyrylcholinesterase, leptophos-oxon, nerve agent, oxime, pesticide, reactivator, scavenger,
• MeSH
• acetylcholinesterasa chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• erytrocyty účinky léků   enzymologie   MeSH
• leptofos analogy a deriváty   chemie   farmakologie   MeSH
• lidé MeSH
• oximy chemie   MeSH
• pesticidy chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• leptofos MeSH
• leptophos oxon MeSH Prohlížeč
• oximy MeSH
• pesticidy MeSH