Abstract
O-glycoprotein 2-acetamino-2-deoxy-beta- d-glucopyranosidase ( O-GlcNAcase) hydrolyzes 2-acetamido-2-deoxy-beta- d-glucopyranose ( O-GlcNAc) residues of serine/threonine residues of modified proteins. O-GlcNAc is present in many intracellular proteins and appears to have a role in the etiology of several diseases including cancer, Alzheimer's disease, and type II diabetes. In this work, we have carried out molecular dynamics simulations using a hybrid quantum mechanics/molecular mechanics approach to determine the binding of two potent inhibitors, PUGNAc and NAG, with a bacterial O-GlcNAcase. The results of these simulations show that Asp-401, Asp-298, and Asp-297 residues play an important role in the protein-inhibitor interactions. These results might be useful to design compounds with more interesting inhibitory activity on the basis of its three-dimensional structure.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosamine / analogs & derivatives*
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Acetylglucosamine / chemistry
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Acetylglucosamine / metabolism
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Acetylglucosamine / pharmacology
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Binding Sites
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Biocatalysis / drug effects
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Ligands
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Models, Molecular*
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Molecular Conformation
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Oximes / chemistry*
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Oximes / metabolism
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Oximes / pharmacology
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Phenylcarbamates / chemistry*
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Phenylcarbamates / metabolism
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Phenylcarbamates / pharmacology
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Protein Binding
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Protons
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Quantum Theory*
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Static Electricity
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Thermodynamics
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Thiazoles / chemistry*
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Thiazoles / metabolism
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Thiazoles / pharmacology
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beta-N-Acetylhexosaminidases / antagonists & inhibitors*
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beta-N-Acetylhexosaminidases / chemistry*
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beta-N-Acetylhexosaminidases / metabolism
Substances
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Enzyme Inhibitors
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Ligands
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Oximes
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Phenylcarbamates
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Protons
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Thiazoles
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N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime
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hexosaminidase C
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beta-N-Acetylhexosaminidases
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N-acetylglucosamine thiazoline
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Acetylglucosamine