Inhibition of β -site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via specific structure-activity relationship with a strong BBB permeability

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Gil Hong Park, Susoma Jannat, Anand Balupuri, Md Yousof Ali, Seong Su Hong, Chun Whan Choi, Yun-Hyeok Choi, Jin-Mo Ku, Woo Jung Kim,Jae Yoon Leem, Ju Eun Kim, Abinash Chandra Shrestha, Ha Neul Ham, Kee-Ho Lee, Dong Min Kim and Nam Sook Kang

Korea University, Korea
Chungnam National University, Korea
Gyeonggido Business & Science Accelerator, Korea
Woosuk University, Korea
Korea Institute of Radiological and Biomedical Sciences, Korea
Jeonju University, Ko

: Arch Clin Pathol

Abstract

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We extracted 15 pterosin derivatives from Pteridium aquilinum inhibiting 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 IC50 of 29.6, 16.2 and 48.1 μM, respectively. 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 and a mixedtype inhibitor against AChE, binding to the active sites of corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE and BChE revealed the novel binding site-directed inhibition of the enzymes by pterosins and structureactivity relationship. (2R)-Pterosin B exhibited a strong BBB permeability with the effective permeability (Pe) of 60.3 × 10-6 cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3R)-pteroside C significantly decreased the secretion of Aβ peptides from neuroblastoma cells overexpressing human β-Amyloid Precursor Protein at 500 μM. Conclusively, our study suggested that a few pterosins are potential scaffolds for multi-target-directed ligands (MTDLs) for AD therapeutics.

Biography

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Gill Hong Park is working in Department of Biochemistry and Molecular Biology, College of Medicine, Korea Molecular Medicine and Nutrition Research Institute, Korea University, Seoul 02841, Korea.

E-mail: ghpark@korea.ac.kr