Polymethoxyflavones: Novel β-Secretase (BACE1) Inhibitors from Citrus Peels.

Abstract

Beta-site amyloid precursor protein (APP) cleaving enzyme1 (BACE1) catalyzes the rate-limiting step of amyloid-β protein (Aβ) generation, and is considered as a prime target for Alzheimer's disease (AD). In search of a candidate for AD prevention, our efforts exploring the natural BACE1 inhibitor have led to the finding of nobiletin, tangeretin, and sinensetin-representative compounds of polymethoxyflavones (PMFs). Tangeretin exhibited the strongest BACE1 inhibition (IC50, 4.9 × 10-5 M), followed by nobiletin and sinensetin with IC50 values of 5.9 × 10-5 M and 6.3 × 10-5 M, respectively. In addition, all compounds reacted in a non-competitive manner with the substrate. Docking analysis results for complexes with BACE1 indicated that SER10 and THR232 residues of BACE1 hydrogen bonded with two oxygen atoms of tangeretin, while three additional BACE1 residues (ALA157, VAL336 and THR232) interacted with three oxygen atoms of nobiletin. Furthermore, sinensetin formed four hydrogen bonds through nitrogen atoms of TYR71, LYS75, and TRP76, and an oxygen atom of TYR198. Furthermore, the lowest-energy conformations of the most proposed complexes of sinensetin, nobiletin, and tangeretin with BACE1 were -7.2, -7.0, and -6.8 kcal/mol, respectively. Taken together, our results suggest that these polymethoxyflavones (PMFs) might be considered as promising BACE1 inhibitory agents that could lower Aβ production in AD.

• Authors: Kumju Youn, Yoonjin Yu, Jinhyuk Lee, Woo-Sik Jeong, Chi-Tang Ho, Mira Jun
• Journal: Nutrients (Nutrients) Vol. 9 Issue 9 (Sep 04 2017) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 28869548 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Flavones
• Flavonoids
• Protease Inhibitors
• sinensetin
• nobiletin
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human
• tangeretin

Topics

• Alzheimer Disease (drug therapy, enzymology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, chemistry, metabolism)
• Aspartic Acid Endopeptidases (antagonists & inhibitors, chemistry, metabolism)
• Citrus (chemistry)
• Dose-Response Relationship, Drug
• Flavones (chemistry, isolation & purification, pharmacology)
• Flavonoids (chemistry, isolation & purification, pharmacology)
• Fruit (chemistry)
• Humans
• Hydrogen Bonding
• Kinetics
• Molecular Docking Simulation
• Protease Inhibitors (chemistry, isolation & purification, pharmacology)
• Protein Binding
• Protein Conformation
• Structure-Activity Relationship