Cholinesterases inhibited by novichok agents - in silico study of reactivation possibilities

Title: Cholinesterases inhibited by novichok agents - in silico study of reacti- vation possibilities Author: Zbyněk Večeřa Department: Department of Organic and Bioorganic Chemistry Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Advisor: PharmDr. Mgr. Tomáš Kučera, Ph.D. Abstract: Substances known as Novichok agents are banned chemical warfare agents, which were developed in Soviet Union between the 1970s and the 1980s. They were brought to the public attention very recently - they were used to po- ison a double agent named Skripal in 2018 and again in 2020 to poison Russian politician Navalny. It is the 4th generation of nerve agents which cause cholinergic syndrome by irreversible inhibition of acetylcholinesterase (AChE), manifesting symptoms such as depression of bronchial tubes, cramps or even paralysis of re- spiratory muscles and depression of the respiratory control centre in the brain. Victim then dies of asphyxiation unless antidotes are administered as soon as possible. Treatment of nerve agents induced poisoning is based on reactivating AChE by oxime compounds which bind themselves with the toxic substance by nucle- ophilic attack on electropositive point of the nerve agent, releasing acetylcholi- nesterase that can continue with function of acetylcholine hydrolysis. The task was to..