Abstract
Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.
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 / isolation & purification
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry*
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Aspartic Acid Endopeptidases / isolation & purification
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Cell Line
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Crystallography, X-Ray
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Cytosine / analogs & derivatives*
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Cytosine / chemistry
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Drug Design*
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Enzyme Inhibitors / chemistry*
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Humans
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Structure
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Recombinant Fusion Proteins / antagonists & inhibitors
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / isolation & purification
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Recombinant Fusion Proteins
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isocytosine
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Cytosine
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Endothia aspartic proteinase
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BACE1 protein, human