Seong_2018_Life.Sci_210_20

AIMS: Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti-Alzheimer's disease (AD) and anti-glycation potential of moracin derivatives. MAIN METHODS: We designed the current study to explore the anti-AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO(-) and ABTS(+) radicals, and their anti-diabetic activity through inhibition of advanced glycation end-products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer-assisted drug design and modeling program. KEY FINDINGS: Among the four Morus-derived moracins tested, moracin S, which has a prenyl moiety in the 2-aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose-dependent fashion, decreased ONOO(-)-mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross-beta structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. SIGNIFICANCE: The prenyl moiety in the 2-aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti-AD drugs.