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 aged Ser-203 residue and a diverse library of QMPs can be examined <i>in silico</i>. From this critical series of computational experiments, promising compounds can then be identified, synthesized, and tested to discover a lead compound based on observed trends.<br/>

Molecular modeling studies on the realkylation of Aged-Acetylcholinesterase (AChE) by Quinone Methide Precursors (QMPs)

253rd National Meeting (2017)

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