Discovery of polymethoxyflavones from black ginger (Kaempferia parviflora) as potential beta-secretase (BACE1) inhibitors

Inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) has emerged as a prime target in Alzheimer's disease research because BACE1 is the rate-limiting enzyme involved in the abnormal production of beta-amyloid peptides. In the course of exploring natural BACE1 inhibitors, the present study focused on the major polymethoxyflavones from Kaempferia parviflora: 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF). All polymethoxyflavones exhibited strong BACE1 inhibitory potency, with no significant suppression of alpha-secretase or other serine protease activities, indicating that they were relatively specific and selective BACE1 inhibitors. Dixon and Lineweaver-Burk plots indicated that they produced non-competitive inhibition of substrate cleavage. An in silico docking study of human BACE1 with polymethoxyflavones demonstrated the binding energy and the interacting residues. Our findings indicated that Kaempferia parviflora could provide a novel therapy for the prevention of Alzheimer's disease and provide a scaffold for exploration of more potent natural BACE1 inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.