Inhibition of Β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and Cholinesterases by Pterosins Via a Specific Structure−activity Relationship with a Strong BBB Permeability

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer’s disease (AD). (2 R )-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC 50 of 29.6, 16.2 and 48.1 µM, respectively. The K i values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC 50 values. (2 R )-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE, and BChE indicated novel binding site-directed inhibition of the enzymes by pterosins and the structure−activity relationship. (2 R )-Pterosin B exhibited a strong BBB permeability with an effective permeability ( P e ) of 60.3×10 −6 cm/s on PAMPA-BBB. (2 R )-Pterosin B and (2 R ,3 R )-pteroside C significantly decreased the secretion of Aβ peptides from neuroblastoma cells that overexpressed human β-amyloid precursor protein at 500 μM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.