%0 Journal Article
%T Inhibition of ¦Â-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure£¿activity relationship with a strong BBB permeability
%J -
%D 2019
%R https://doi.org/10.1038/s12276-019-0205-7
%X We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited ¦Â-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer¡¯s disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1£¿¦ÌM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-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. (2R)-Pterosin B exhibited a strong BBB permeability with an effective permeability (Pe) of 60.3¡Á10£¿6£¿cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3£¿R)-pteroside C significantly decreased the secretion of A¦Â peptides from neuroblastoma cells that overexpressed human ¦Â-amyloid precursor protein at 500£¿¦ÌM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics
%U https://www.nature.com/articles/s12276-019-0205-7