Mechanistic Insights into the Alkylation Reactions of Quinone Methide Precursors: Studies Towards the Realkylation of Aged Acetylcholinesterase

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Acetylcholinesterase (AChE) is an essential enzyme in the human body, which hydrolyzes the neurotransmitter acetylcholine into choline and acetate at neurosynaptic junctions. Organophosphorus (OP) nerve agents such as Sarin, Soman, and Tabun are covalent inhibitors of AChE. Following exposure to OPs, AChE is inhibited and undergoes a subsequent irreversible aging process in which the OP-AChE adduct is de-alkylated, resulting in the accumulation of excess acetylcholine in the central nervous system. Current oxime-based pharmaceuticals can only be used to treat the inhibited AChE and are ineffective on the aged AChE. Our research focuses on re-activation of the aged AChE. Quinone methides (QM) have been shown to react with phosphates to form an O–C bond, and such structures may potentially reverse the damage done to the active site on aged AChE through a kinetically favored alkylation of the phosphylated serine residue in aged AChE. Computational methods were used to analyze the potential reaction pathways and docking poses in AChE of a variety of quinone methide precursors (QMPs). 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 have also been performed to determine how the interaction between ligand and enzyme changes over time. Statistical analysis of these molecular dynamics trajectories has allowed our collaborative effort to identify potential lead compounds that stand the best chance of staying in proximity of the target aged serine residue. The analysis of these results has provided guidance to which potential therapeutics should be investigated further due to their favorable interaction with the target active site.


Mathematical and Physical Sciences: 1st Place (The Ohio State University Denman Undergraduate Research Forum)


Computational Chemistry, Quinone Methides, Acetylcholinesterase, AChE, Quinone Methide Precursors, Alkylation