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

Abstract

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). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC₅₀ 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 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 (P_e) of 60.3×10⁻⁶ cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,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.

Alzheimer’s disease: Promising therapeutic compounds found in plants

Compounds extracted from bracken fern block the activity of three enzymes associated with Alzheimer’s disease (AD). Because AD is a complex and multifactorial disease, a multitarget-directed approach is an attractive strategy for the development of disease-modifying therapeutics. A study led by Gil Hong Park, Korea University, Seoul, and Nam Sook Kang, Chungnam National University, Daejon, revealed that pterosin derivatives could reduce the activity of β-site amyloid precursor protein cleaving enzyme 1, acetylcholinesterase and butyrylcholinesterase in a concentration-dependent manner. Furthermore, the fern-extracted compounds did not cause cellular toxicity and were able to cross the blood–brain barrier, which is impermeable to most drugs, to reach the brain. Future studies will determine whether they can be developed into drugs to simultaneously engage various AD targets in animal models of the disease.