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PC-28

Rapid identification of natural acetylcholinesterase inhibitors from

Glycosmis parviflora stem utilizing dereplication, in vitro and in silico

approach

1
1,2
3
3
Truc-Ly Thi Duong, T a -Wei Liu, Quoc-Dung Tran Huynh, Dang-Khoa Nguyen,
3
1
4
,3
Yun-Han Wang, Man-Hsiu Chu, Thanh-Hoa Vo, Su-Jung Hsu,* Ching-Kuo Lee* ,1,3,5

1 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy,
Taipei Medical University, Taipei 11031, Taiwan
2 Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam
3 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
4 School of Medicine, Vietnam National University Ho Chi Minh City, Ho Chi Minh City
700000, Vietnam
5 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei
11031, Taiwan
* E-mail: juliashu1101@gmail.com; cklee@tmu.edu.tw; Tel.: +889-2736-1661-6150

Abstract
Acetylcholinesterase (AChE) inhibition is a significant strategy for preventing Alzheimer's
disease (AD) and neurodegenerative diseases. In this study, a dereplication system was utilized
to rapidly identify and characterize AChE-interacting compounds by comparing UPLC-MS/MS
profile screening approach and molecular docking analysis, derived from the extracts and
fractions of the stem of Glycosmis parviflora (Sims) Little. Eleven potential AChE inhibitors
were identified from the ethyl acetate extract of G. parviflora, including an undescribed alkaloid
(9), glybomine D, eight known alkaloids (1−8), a flavonoid (10), and a phytosterol (11). The
inhibitory of these compounds against AChE was assessed, with O-methylglycosolone (6), 1,3-
dimethoxy-2-hydroxy-10-methyl-9(10H)-acridinone (1), skimmianine (4) and arborine (2),
regarded as effective inhibitors, yielding IC50 values of 39.81 μM, 41.53 μM, 49.40 μM, and
59.92 μM, respectively. Notably, O-methylglycosolone exhibited the highest potency. Four of
these potent AChE inhibitors exhibited mixed-type inhibition. However, O-methylglycosolone
(6), 1,3-dimethoxy-2-hydroxy-10-methyl-9(10H)-acridinone (1), and arborine (2) were first
reported modulating with acetylcholinesterase activity. Furthermore, molecular docking
revealed O-methylglycosolone (6) superior binding affinity (-23.749 kcal/mol) compared to
other compounds, mainly by interacting with the peripheral anionic site of AChE, which forms
hydrogen bonds and hydrophobic forces may play an important role, interaction with amino
acid in the active cavity, which is crucial for effective and selective inhibition of AChE activity.
ADMET predictions suggest that arborine (2), skimmianine (4), and O-methylglycosolone (6)
demonstrate favorable permeability across the blood-brain barrier, while 1,3-dimethoxy-2-
hydroxy-10-methyl-9(10H)-acridinone (1) exhibits comparatively reduced permeability. These
findings highlight the potential of these compounds as natural AChE inhibitors for treating
neurodegenerative diseases.

Keywords: Glycosmis parviflora; Alzheimer's disease; Acetylcholinesterase inhibitor;
Dereplication; Molecular docking