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

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, Nam Sook Kang, Gil Hong Park

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6 Citations (Scopus)

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 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. (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.

Original languageEnglish
Article number12
JournalExperimental and Molecular Medicine
Volume51
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Jannat, S., Balupuri, A., Ali, M. Y., Hong, S. S., Choi, C. W., Choi, Y. H., Ku, J. M., Kim, W. J., Leem, J. Y., Kim, J. E., Shrestha, A. C., Ham, H. N., Lee, K. H., Kim, D. M., Kang, N. S., & Park, G. H. (2019). 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. Experimental and Molecular Medicine, 51(2), [12]. https://doi.org/10.1038/s12276-019-0205-7