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

• Published in: Biochimica et biophysica acta Vol. 1780; no. 5; pp. 819 - 825
• Main Authors: Shimmyo, Yoshiari, Kihara, Takeshi, Akaike, Akinori, Niidome, Tetsuhiro, Sugimoto, Hachiro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2008
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Animals; Apigenin - chemistry; Apigenin - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; BACE-1; Catalytic Domain; Cell Survival - drug effects; Cerebral Cortex - cytology; Flavones - chemistry; Flavones - pharmacology; Flavonoid; 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; Pharmacophore; Primary neuron; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Quercetin - chemistry; Quercetin - pharmacology; Rats; Structure-Activity Relationship; Aβ; Primary neuron; Flavonoid; Alzheimer's disease; Pharmacophore; BACE-1
• DOI: 10.1016/j.bbagen.2008.01.017
• ISSN: 0304-4165; 0006-3002

Generation and accumulation of the amyloid β peptide (Aβ) following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 (Beta-site APP Cleaving Enzyme-1, β-secretase) and γ-secretase is a main causal factor of Alzheimer's disease (AD). Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Aβ, 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 Aβ 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.