Organophosphorus compounds (OPs) are toxic nerve agents used in chemical warfare. These OPs covalently bond with Serine-203, a main catalytic residue in acetylcholinesterase (AChE), to prevent the hydrolysis of the neurotransmitter acetylcholine. After a given period of time depending on the OP compound, the now inhibited AChE will undergo an irreversible process known as aging, where the OP-AChE moiety will dealkylate and form a stable phosphonate anion permanently inactivating the enzyme. Without functioning AChE, acetylcholine accumulates in the neuromuscular junction and affected individuals can experience muscle spams and eventually death by asphyxiation. Currently, there are no known therapeutic methods to reverse this aging process and regain enzymatic activity. However, inhibited AChE can be restored to the active form before it becomes aged by pharmaceuticals containing an oxime functional group. The goal of this project is to discover a compound that will realkylate the stable phosphonate anion on Ser-203 in aged-AChE, which can then be restored to the active AChE by oximes. Literature precedent shows that quinone methides (QMs) are capable of alkylating phosphodiesters, which are structurally similar to the phosphonylated Ser-203 residue in the aged-AChE active site. Through computational analysis via molecular docking and molecular dynamics, the chemical interactions between the Ser-203 residue and a diverse library of QMPs have been examined in silico. From this critical series of computational experiments, promising compounds have been identified, synthesized, and tested to discover a lead compound based on observed trends.

Computational studies on the realkylation of aged acetylcholinesterase (AChE) by quinone method precursors (QMPs)

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.