(116ao) Kinetic Evaluation of Bifunctional Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) to terminate nerve signal transmission in the central and peripheral nervous systems. A consequence of Alzheimer's disease is the depletion of ACh concentrations in the brain, resulting in a decrease in the brain's capacity to transmit nerve signals and associated cognition impairment. In order to combat the depletion of ACh, our research group is focusing on the design and optimization of AChE inhibitors. The blueprint for drug design includes a meta-substituted aryl trifluoromethyl ketone functional group that targets the active site of AChE. Inhibitor variants are created through the use of nitrogen-based connectors of different lengths that include an aryl, substituted aryl, or other moiety that targets the peripheral site of AChE. My individual research role focuses on the kinetic evaluation of inhibitors through UV-VIS spectroscopy. Reaction rate data are first used to determine the inhibitor concentration causing a 50% reduction in ACh turnover. Additional assays yield rate constants for slow, tight binding inhibition, as well as the overall residence time of the inhibitor on the enzyme. The results of the kinetic analyses indicate superior peripheral-site moieties and direct improvements in inhibitor design.