A Comprehensive Review of Cholinesterase Modeling and Simulation

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.

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

“…Several studies based on molecular modeling and computer simulations appeared in the literature, to aid the experimental research in the efforts to design efficient oximes for the deactivation of a broad spectrum of OP compounds, as no single oxime available in the market can target the broad spectrum of OP derivatives [62][63][64]. For instance, docking studies and DFT calculations, conducted by Ramalho et al, demonstrated that the theoretical data aligned well with the experimental results, in the prediction of free energies of oximes that can further aid in designing effective oximes targeting AChE [65].…”

In Silico and Ex Vivo Analyses of the Inhibitory Action of the Alzheimer Drug Posiphen and Primary Metabolites with Human Acetyl- and Butyrylcholinesterase Enzymes

“…This is achieved by the cholinesterase (ChE) enzymes that cleave ACh into choline and acetic acid . Two classes of cholinesterase enzymes coexist throughout the body and play a range of both cholinergic and non-cholinergic roles that are determined by their time and volume of expression, location, and particular subtype. , Within the healthy human brain, acetylcholinesterase (AChE; EC 3.1.1.7.) dominates and accounts for some 90% of cholinesterase activity, with butyrylcholinesterase (BChE; EC 3.1.1.8) providing the remainder.…”

Spatial Distribution and Stability of Cholinesterase Inhibitory Protoberberine Alkaloids from Papaver setiferum

“… 1 , 4 Both cholinesterases can catalyze the hydrolysis of acetylcholine to terminate neurotransmitter activity and signal transduction. 3 − 6 …”

“…3.1.1.7, or “true cholinesterase”) is a serine hydrolase that catalyzes the hydrolysis of the neurotransmitter acetylcholine. In mammals, AChE is present in cholinergic synapses of the central, peripheral, and autonomic nervous systems and in neuromuscular junctions and erythrocytes. − Butyrylcholinesterase (BChE, E.C. 3.1.1.8, previously called pseudocholinesterase) is a nonspecific cholinesterase that hydrolyzes a variety of choline and noncholine esters and is found primarily in plasma and in the liver. , Both cholinesterases can catalyze the hydrolysis of acetylcholine to terminate neurotransmitter activity and signal transduction. − …”

“…In mammals, AChE is present in cholinergic synapses of the central, peripheral, and autonomic nervous systems and in neuromuscular junctions and erythrocytes. − Butyrylcholinesterase (BChE, E.C. 3.1.1.8, previously called pseudocholinesterase) is a nonspecific cholinesterase that hydrolyzes a variety of choline and noncholine esters and is found primarily in plasma and in the liver. , Both cholinesterases can catalyze the hydrolysis of acetylcholine to terminate neurotransmitter activity and signal transduction. − …”