Abstract
Generation and accumulation of the amyloid beta peptide (Abeta) following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 (Beta-site APP Cleaving Enzyme-1, beta-secretase) and gamma-secretase is a main causal factor of Alzheimer's disease (AD). Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Abeta, is an attractive therapeutic approach for the treatment of AD. In this study, we discovered that natural flavonoids act as non-peptidic BACE-1 inhibitors and potently inhibit BACE-1 activity and reduce the level of secreted Abeta in primary cortical neurons. In addition, we demonstrated the calculated docking poses of flavonoids to BACE-1 and revealed the interactions of flavonoids with the BACE-1 catalytic center. We firstly revealed novel pharmacophore features of flavonoids by using cell-free, cell-based and in silico docking studies. These results contribute to the development of new BACE-1 inhibitors for the treatment of AD.
MeSH terms
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Alzheimer Disease / drug therapy
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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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Amyloid beta-Peptides / metabolism
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Animals
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Apigenin / chemistry
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Apigenin / pharmacology
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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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Catalytic Domain
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Cell Survival / drug effects
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Cerebral Cortex / cytology
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Flavones / chemistry
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Flavones / pharmacology*
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Flavonoids / chemistry
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Flavonoids / pharmacology
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Flavonols / chemistry
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Flavonols / pharmacology*
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Humans
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Hydrogen Bonding
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Kaempferols / chemistry
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Kaempferols / pharmacology
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Models, Molecular*
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Molecular Structure
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Quercetin / chemistry
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Quercetin / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Flavones
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Flavonoids
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Flavonols
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Kaempferols
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Protease Inhibitors
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kaempferol
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myricetin
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Apigenin
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morin
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Quercetin
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human