1 Department of Biochemistry and Molecular Biology, College of Medicine, Korea Molecular Medicine and Nutrition Research Institute, Korea University, Seoul, 02841, Korea.
2 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Korea.
3 Department of Chemistry and Biochemistry, Faculty of Arts and Science, Concordia University, 7141 Sherbrooke St. W., Montreal, QC, H4B 1R6, Canada.
4 Center for Structural and Functional Genomic, Department of Biology, Faculty of Arts and Science, Concordia University, 7141 Sherbrooke St. W., Montreal, QC, H4B 1R6, Canada.
5 Bio-Center, Gyeonggido Business & Science Accelerator, Suwon, 16229, Korea.
6 College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Korea.
7 Division of Radiation Cancer Research, Korea Institute of Radiological and Biomedical Sciences, Seoul, 01812, Korea.
8 Department of Creative Arts Psychotherapy, College of Cultural Convergence, Jeonju University, Jeonju, 55069, Korea.
9 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Korea. nskang@cnu.ac.kr.
10 Department of Biochemistry and Molecular Biology, College of Medicine, Korea Molecular Medicine and Nutrition Research Institute, Korea University, Seoul, 02841, Korea. ghpark@korea.ac.kr.

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

Exp Mol Med. 2019 02 12;51(2):12

Authors: Jannat S, Balupuri A, Ali MY, Hong SS, Choi CW, Choi YH, Ku JM, Kim WJ, Leem JY, Kim JE, Shrestha AC, Ham HN, Lee KH, Kim DM, Kang NS, Park GH

Abstract

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited ß-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 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 60.3×10-6?cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3?R)-pteroside C significantly decreased the secretion of Aß peptides from neuroblastoma cells that overexpressed human ß-amyloid precursor protein at 500?µM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.

PMID: 30755593 [PubMed - in process]