Acetylcholinesterase (AChE) is an essential enzyme in the human body. It hydrolyzes the neurotransmitter acetylcholine intocholine and acetate at neurosynaptic junctions. Organophosphorus (OP) nerve agents such as Sarin and Soman 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 model phosphates to alkylate them, and therefore 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 human aged-AChE were used for our docking calculations, in which the QMPs were allowed to interact with the enzyme active site. Certain poses were further investigated using molecular dynamics simulations to better understand the interaction between ligand and enzyme. The analysis of these results has provided guidance to which potential therapeutics should be investigated further.

Mechanistic insights into the alkylation reactions of quinone methide precursors: Studies towards the realkylation of aged acetylcholinesterase

249th National Meeting (2015)

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