Abstract
Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 microM) and 6c (IC50 = 24 microM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).
MeSH terms
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Aminoquinolines / chemical synthesis
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Aminoquinolines / chemistry*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry*
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry*
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Binding Sites
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Crystallography, X-Ray
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Ligands
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Models, Molecular*
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Protein Binding
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Quantitative Structure-Activity Relationship*
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
Substances
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Aminoquinolines
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Indoles
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Ligands
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Recombinant Proteins
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
Associated data
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PDB/2OHP
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PDB/2OHQ
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PDB/2OHR
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PDB/2OHS
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PDB/2OHT
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PDB/2OHU