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KMID : 0620920190510020012
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Experimental & Molecular Medicine
2019 Volume.51 No. 2 p.12 ~ p.12
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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
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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
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Abstract
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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 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 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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KEYWORD
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Alzheimer's disease, Biologics
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