Acetylcholinesterase (AChE) is an enzyme responsible for the hydrolysis of acetylcholine in the synaptic cleft between neurons and at the neuromuscular junction. Acetylcholine is a neurotransmitter that is essential for nerve function, acting as an on-switch that leads to contraction of the associated muscles in the neuromuscular junction or stimulation of the post-synaptic neuron in the synaptic cleft. AChE acts as the off-switch, regulating the effects of acetylcholine in neurostimulation. Organophosphorus (OP) compounds are a family of molecules that react with the active site serine in AChE, rendering it inactive, and thus causing a build-up of acetylcholine in the central and peripheral nervous system, leading to cholinergic crisis and eventually death. Such OP compounds include soman, sarin, and tabun, which are classified as nerve agents due to their dramatic effects on human health. After exposure to an OP, phosphylation of the active site serine residue in AChE occurs, bringing the enzyme to an OP-inhibited state. The OP-inhibited AChE can also go through a subsequent dealkylation process where it becomes aged; at which point, the OP-aged AChE enzyme has been considered to be irreversibly inactivated. Current treatments for OP exposure include oximes, but they are only effective when restoring the activity of the OP-inhibited form of AChE. To date, there are no approved treatments for restoring the activity of the OP-aged enzyme and until recently no compounds had been shown to restore activity <i>in vitro</i>. Our research team reported preliminary success in recovering activity from the OP-aged state of the enzyme through the use of quinone methide precursors (QMPs). While current efforts are underway to improve the activity of this family of compounds and to find more ideal therapeutics, it is important to begin to examine the toxicological properties of these QMPs as well as related, potential therapeutics. Two major interfaces, SwissADME and ACD/Percepta, were used for preliminary screening of toxicological properties of these proposed therapeutics. The results from both approaches were used to compare some of the important toxicological properties of our lead QMPs including blood-brain barrier permeability, P-glycoprotein substrate/inhibition, cytochrome P450 substrate/inhibiton, hERG inhibiton, and plasma protein binding. The results from these analyses will be presented.

Toxicology studies of potential therapeutics for the resurrection of the aged form of acetylcholinesterase after exposure to organophosphorus chemical nerve agents

2019 Spring National Meeting

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