Abstract
Owing to its special role as a negative regulator in both insulin and leptin signaling, protein tyrosine phosphatase-1B (PTP1B) has drawn considerable attention as a target for treating type 2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a series of compounds were discovered to inhibit PTP1B based on imidazolidine-2,4-dione by means of 'core hopping'. A selective PTP1B inhibitor (comp#h) was identified, and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes.
Keywords:
PTP1B; core hopping; drug design; molecular dynamics; selective inhibitors.
© 2013 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Diabetes Mellitus, Type 2 / drug therapy
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Drug Design*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Humans
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Imidazolidines / chemistry*
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Imidazolidines / metabolism
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Imidazolidines / pharmacology*
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Imidazolidines / therapeutic use
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Molecular Docking Simulation
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Protein Binding
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 2 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
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Thermodynamics
Substances
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Enzyme Inhibitors
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Imidazolidines
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imidazolidine-2,4-dione
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 2