Flavonols and flavones as BACE-1 inhibitors: structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features

Biochim Biophys Acta. 2008 May;1780(5):819-25. doi: 10.1016/j.bbagen.2008.01.017. Epub 2008 Feb 9.

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

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apigenin / chemistry
  • Apigenin / pharmacology
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / metabolism
  • Catalytic Domain
  • Cell Survival / drug effects
  • Cerebral Cortex / cytology
  • Flavones / chemistry
  • Flavones / pharmacology*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Flavonols / chemistry
  • Flavonols / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Kaempferols / chemistry
  • Kaempferols / pharmacology
  • Models, Molecular*
  • Molecular Structure
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / metabolism
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Quercetin / chemistry
  • Quercetin / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Flavones
  • Flavonoids
  • Flavonols
  • Kaempferols
  • Protease Inhibitors
  • kaempferol
  • myricetin
  • Apigenin
  • morin
  • Quercetin
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human