Computational Study of Butyrylcholinesterase Inhibition by Aryl Alkyl Cholinyl Phosphorus Derivatives

Abstract

Acetylcholine (ACh) is a neurotransmitter that is released from nerve cells to send signals to other cells, and acetylcholinesterase (AChE) is a highly specific enzyme that hydrolyzes ACh to regulate intercellular communication. However, butyrylcholinesterase (BChE), a non-specific AChE imposter, also breaks down choline based esters such as ACh. The activity of BChE has been found to gradually increase over time in patients with Alzheimer's disease (AD), which has been linked to a significant decrease in synaptic ACh levels, thus disrupting intercellular communication. In the treatment of AD, discovering inhibitors that prevent the activity of BChE and that do not interfere with the activity of AChE is vital. Aryl alkyl cholinyl phosphorous (AACP) derivatives are organophosphates that are expected to reversibly bind within the BChE binding pocket in the same manner as natural physiological substrates. This study utilizes massive flexible inhibitor docking calculations to predict the relative binding affinities between the enzyme and a number of AACP derivatives and to predict the optimal binding orientation(s) of each AACP derivative within the BChE active site. When compared to their previously studied dialkyl phenyl phosphate (DAPP) analogs, AACP derivatives are predicted to interact more strongly with the binding site of BChE, thus serving as more potent inhibitors. Our results reproduce experimental trends in binding affinity, indicating that derivatives with longer alkyl chains show increased inhibitory strength (as observed for DAPP derivatives), and the neutralization of the charge of the choline group and protonation of the neutral choline group had little effect on inhibitor strength, offering insight into the structural preferences of BChE for specific AACP derivatives. This study thus provides a framework for both future inhibitor design and more rigorous molecular dynamics studies of cholinesterase-inhibitor interaction.