Organophosphorus compounds (OPs) such as sarin, soman, and tabun are toxic nerve agents used in chemical warfare. These OPs covalently bond with Serine-203 (Ser203), a catalytic residue in the enzyme acetylcholinesterase (AChE), preventing hydrolysis of the neurotransmitter acetylcholine into acetate and choline. Once exposed to an OP compound, the inhibited AChE will undergo an irreversible process known as aging, where the OP-AChE complex will dealkylate and form a stable phosphonate anion on the serine residue, permanently inactivating the enzyme. Without functioning AChE, acetylcholine accumulates in the central nervous system causing seizures vomiting and often death. Currently, there are no known therapeutic methods to reverse this aging process to regain enzymatic activity. However, inhibited AChE can be restored to the active AChE before the onset of the aging process by treatment with pharmaceuticals containing an oxime functional group. The goal of this project is to discover a compound that will re-alkylate the phosphonate anion on Ser203 in aged-AChE, which can then be restored to the active AChE by oxime treatment. Literature shows that quinone methides (QMs) are capable of alkylating phosphodiesters, which are structurally similar to the phosphonylated Ser203 residue in the aged-AChE active site. Through computational methods, potential docking poses in AChE of a variety of quinone methide precursors (QMPs) were analyzed in silico. These QMPs were chosen as derivatives of a lead compound. Snapshots of an aged AChE were used for our docking calculations where the QMPs were allowed to interact with the enzyme active site. Molecular dynamics simulations permitted us to determine how the interaction between the ligand and enzyme changed over time. Statistical analysis of the results from these computational studies provided insight into structural characteristics of the most effective QMPs, which our colleagues can then combine and synthesize to make the most promising compounds for in vitro analysis with the goal of eventually creating a therapeutic agent.

Computational simulations of realkylation reactions of aged-acetylcholinesterase with quinone methide precursors

255th National Meeting (2018)

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