Abstract
Fragment screening revealed that tyramine binds to the active site of the Alzheimer's disease drug target BACE-1. Hit expansion by selection of compounds from the Roche compound library identified tyramine derivatives with improved binding affinities as monitored by surface plasmon resonance. X-ray structures show that the amine of the tyramine fragment hydrogen-bonds to the catalytic water molecule. Structure-guided ligand design led to the synthesis of further low molecular weight compounds that are starting points for chemical leads.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / metabolism*
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / chemistry
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Aspartic Acid Endopeptidases / metabolism*
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Binding Sites
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Crystallography, X-Ray
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Humans
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Kinetics
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Models, Molecular
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism*
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Protein Binding
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Protein Conformation
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Tyramine / chemistry
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Tyramine / metabolism*
Substances
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Peptide Fragments
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Tyramine