Abstract
The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes.
Highlights
The cholinesterase enzyme family has but two members: acetylcholinesterase (AChE)and butyrylcholinesterase (BChE)
Steric and electrostatic interactions may slow the catalytic efficiency of AChE, the peripheral aromatic site (PAS) is valuable for trafficking ligands into the gorge [39], positively charged species such as cholines
Simulations have emphasized the importance of cation-π interactions, which stabilize the ligand at the rim of the gorge entrance prior to entering the gorge [40], and it has been proposed that non-cholinergic activity of the PAS could include the deposition of amyloids, adhesion to cells, and outgrowth of neurites [41]
Summary
Danna De Boer 1,† , Nguyet Nguyen 2,† , Jia Mao 2 , Jessica Moore 3 and Eric J. Authors wish it to be known that the first two authors contributed to this work
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