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Acetylcholinesterase (AChE) inhibitors are the primary target for single-molecule anti-Alzheimer’s disease (AD) therapeutics. Though AChE has historically been the focus of investigation for small-molecule inhibitors, interest in another cholinergic enzyme, butyrylcholinesterase (BChE), has grown in recent years. Attention stems from BChE’s role in β-amyloid (Aβ) protein aggregation and an increase in BChE concentration during the late stages of AD, where a decrease in AChE concentration is also observed. Currently, five FDA-approved drugs are on the market for inhibiting AChE, though no BChE-selective drugs have been approved so far. In this review, we focus on newly identified BChE selective inhibitors and present the ideas behind these discoveries. © 2025 by the authors.
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The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer’s Disease progresses from the mid-to-late stage and from butyrylcholinesterase’s (BChE) role in β-amyloid plaque formation. While structure-based and pharmacophore-based virtual screening could search from large libraries in a short time, these methods do not consider dynamic features that result from a ligand’s inhibition of the enzyme and consequently may under- or overexaggerate enzyme selectivity of a given ligand. In this computational study, we probed the selectivity of representative secondary metabolite compounds against acetylcholinesterase and BChE through molecular dynamics simulations. The results were evaluated by analysis of the root mean squared deviation of ligand heavy atoms, the radius of gyration of each inhibited and uninhibited enzyme, root mean squared fluctuation of residues, intermolecular interaction energy, and linear interaction energy approximation of the Gibbs free energy of binding. These considerations further reveal the induced-fit characteristics contributing to ChE selectivity that are predominantly due to the greater flexibility of BChE’s active site gorge. © 2025 by the authors.
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Sea lamprey (Petromyzon marinus) is a unique vertebrate model to examine how liver metabolomes support different reproductive functions. Juvenile sea lamprey prey on other fish species by attaching to their body and feeding on their blood and body fluids. Once reaching adulthood, they cease feeding, migrate to spawning streams and begin their final sexual maturation. During these processes, the male livers produce large quantities of bile acid pheromone precursors to be modified and released via gills, whereas the female livers synthesize vast amounts of vitellogenin (yolk lipophosphoprotein) to be transported to the ovary.
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Migratory fishes are renowned for their ability to home to natal streams for spawning. Learned olfactory cues play a critical role in natal homing of Pacific salmon and other fishes, but the underlying chemical signature of streams remains poorly understood after decades of study. The molecules that convey a stream-specific odour must differ among sites but remain constant over time. Among leading odorant candidates are amino acids; however, little research has assessed the spatial and temporal variability of amino acid profiles in streams. We report a comprehensive chemical study of dissolved amino acids as potential olfactory cues for homing by migratory fish. Specifically, we profiled amino acids in water from 23 streams in the upper Laurentian Great Lakes basin over 2 years. We investigated variation in amino acid profiles (1) among regions and rivers within a year, (2) between years and (3) among sites and across the seasons of migration and early life history within a stream. Liquid-chromatography tandem mass spectrometry revealed nanomolar concentrations for most of the 20 L-amino acids measured, above the levels detectable by studied migratory fishes. Moreover, amino acid profiles were temporally stable between 2 years and across an annual season from adult spawning migration through offspring early-life development within a stream. However, spatial differences in amino acid profiles were evident primarily over large geographic distances (among regions) but not among tributaries within regions or among sites within a stream. Collectively, our results indicate dissolved amino acids may be consistent components of rivers' odorant profiles but suggest additional molecules are likely important for natal homing of migratory fishes to specific spawning sites. We suggest that future studies consider the combined importance of amino acids and molecules from other chemical classes. Understanding the chemical basis of olfactory-guided natal homing is especially important as human activities could alter the odorant profiles of streams and thereby disrupt fish migrations and negatively impact population recruitment.