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

Research output: Contribution to journalArticle

2 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

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Butyrylcholinesterase
Amyloid beta-Protein Precursor
Acetylcholinesterase
Permeability
Cholinesterase Inhibitors
Enzymes
Alzheimer Disease
Pteridium
Molecular Docking Simulation
Cholinesterases
Binding energy
Neuroblastoma
Scaffolds
Catalytic Domain
Binding Sites
Ligands
Derivatives
Peptides
pterosin
Inhibition (Psychology)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

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

In: Experimental and Molecular Medicine, Vol. 51, No. 2, 12, 01.02.2019.

Research output: Contribution to journalArticle

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, 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, vol. 51, no. 2, 12. https://doi.org/10.1038/s12276-019-0205-7
Jannat, Susoma ; Balupuri, Anand ; Ali, Md Yousof ; Hong, Seong Su ; Choi, Chun Whan ; Choi, Yun Hyeok ; Ku, Jin Mo ; Kim, Woo Jung ; Leem, Jae Yoon ; Kim, Ju Eun ; Shrestha, Abinash Chandra ; Ham, Ha Neul ; Lee, Kee Ho ; Kim, Dong Min ; Kang, Nam Sook ; Park, Gil-Hong. / 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. In: Experimental and Molecular Medicine. 2019 ; Vol. 51, No. 2.
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AU - Jannat, Susoma

AU - Balupuri, Anand

AU - Ali, Md Yousof

AU - Hong, Seong Su

AU - Choi, Chun Whan

AU - Choi, Yun Hyeok

AU - Ku, Jin Mo

AU - Kim, Woo Jung

AU - Leem, Jae Yoon

AU - Kim, Ju Eun

AU - Shrestha, Abinash Chandra

AU - Ham, Ha Neul

AU - Lee, Kee Ho

AU - Kim, Dong Min

AU - Kang, Nam Sook

AU - Park, Gil-Hong

PY - 2019/2/1

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N2 - 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.

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