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Open AccessCommunication

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

Department of Food Science and Nutrition, Dong-A University, 37, Nakdong-daero 550 beon-gil, Saha-gu, Busan 49315, Korea
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea
Department of Bioinformatics, University of Sciences and Technology, 100, Hyecheon-ro, Seo-gu, Daejeon 34141, Korea
Department of Food & Life Science, College of Biomedical Science & Engineering, Inje University, 197, Inje-ro, Gimhae-si, Gyeongsangnam-do 50834, Korea
Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
Author to whom correspondence should be addressed.
Nutrients 2017, 9(9), 973;
Received: 31 July 2017 / Revised: 22 August 2017 / Accepted: 1 September 2017 / Published: 4 September 2017
(This article belongs to the Special Issue Effects of Polyphenol-Rich Foods on Human Health)
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. View Full-Text
Keywords: Alzheimer’s disease (AD); β-secretase (BACE1); citrus peel; polymethoxyflavones (PMFs) Alzheimer’s disease (AD); β-secretase (BACE1); citrus peel; polymethoxyflavones (PMFs)
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Youn, K.; Yu, Y.; Lee, J.; Jeong, W.-S.; Ho, C.-T.; Jun, M. Polymethoxyflavones: Novel β-Secretase (BACE1) Inhibitors from Citrus Peels. Nutrients 2017, 9, 973.

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