Integrated computational screening and biochemical validation identify natural small molecules targeting Aβ aggregation and dissociation
4 affiliations
- 1School of Pharmacy, Jeonbuk National University , ,
- 2Department of Biochemistry, College of Medicine, Konyang University , ,
- 3College of Pharmacy, Chungnam National University , ,
- 4Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB) , ,
Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ), a pathological hallmark implicated in disease onset and progression. Aβ undergoes self-assembly from monomers into soluble oligomers, protofibrils, insoluble fibrils, and extracellular plaques. Our previous studies have shown that Jowiseungchungtang, which consists of 14 medicinal herbs, inhibits Aβ aggregation and ameliorates Aβ-mediated pathology in AD models. However, the active small molecules underlying these effects remain unidentified. To identify small molecules from these 14 medicinal herbs, we constructed a library of 1,751 compounds and applied an integrated in silico and in vitro workflow. First, these 1,751 compounds were filtered based on drug-likeness and predicted blood-brain barrier permeability, yielding 566 candidates. Second, molecular docking of 566 selected compounds against Aβ conformers identified five candidates predicted to interact with aggregation-prone residues critical for Aβ aggregation and fibril stabilization. Third, Thioflavin T assays demonstrated that four compounds—1-monopalmitin, isobutyl octyl oxalate, pentadecanoic acid, and dimethyl azelate—significantly inhibited Aβ42 aggregation. Additionally, isobutyl octyl oxalate and pentadecanoic acid disaggregated preformed Aβ42 aggregates. Fourth, molecular dynamics simulations were performed to examine the short-timescale behavior of the candidate compounds with the Aβ17–42 dimer, showing transient ligand–Aβ interactions associated with structural rearrangements at the dimer interface. Pharmacokinetic predictions supported drug-likeness, showing blood-brain barrier permeability and systemic clearance. Collectively, these findings identify four Jowiseungchungtang (JWS)-derived candidate compounds with Aβ aggregation-inhibitory activity and provide a mechanistic and pharmacokinetic basis for further development of these compounds as potential therapeutic agents in AD.
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BibTeX
@article{lee2026integrated,
title = {{Integrated computational screening and biochemical validation identify natural small molecules targeting Aβ aggregation and dissociation}},
author = {Hyewon Lee and Vijay Kumar and Soo Jung Shin and Yunkwon Nam and Sinae Jang and Hyeon soo Kim and Minseok Lee and Gyu Yong Song and Eun-Kyung Lim and Han-Jung Chae and Minho Moon},
journal = {Journal of pharmacy \& pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques},
year = {2026},
month = oct,
doi = {10.3389/jpps.2026.17216},
url = {https://europepmc.org/article/PMC/PMC13727513},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrated computational screening and biochemical validation identify natural small molecules targeting Aβ aggregation and dissociation
AU - Hyewon Lee
AU - Vijay Kumar
AU - Soo Jung Shin
AU - Yunkwon Nam
AU - Sinae Jang
AU - Hyeon soo Kim
AU - Minseok Lee
AU - Gyu Yong Song
AU - Eun-Kyung Lim
AU - Han-Jung Chae
AU - Minho Moon
PY - 2026
DA - 2026/10/20
JO - Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques
DO - 10.3389/jpps.2026.17216
UR - https://europepmc.org/article/PMC/PMC13727513
AB - Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ), a pathological hallmark implicated in disease onset and progression. Aβ undergoes self-assembly from monomers into soluble oligomers, protofibrils, insoluble fibrils, and extracellular plaques. Our previous studies have shown that Jowiseungchungtang, which consists of 14 medicinal herbs, inhibits Aβ aggregation and ameliorates Aβ-mediated pathology in AD models. However, the active small molecules underlying these effects remain unidentified. To identify small molecules from these 14 medicinal herbs, we constructed a library of 1,751 compounds and applied an integrated in silico and in vitro workflow. First, these 1,751 compounds were filtered based on drug-likeness and predicted blood-brain barrier permeability, yielding 566 candidates. Second, molecular docking of 566 selected compounds against Aβ conformers identified five candidates predicted to interact with aggregation-prone residues critical for Aβ aggregation and fibril stabilization. Third, Thioflavin T assays demonstrated that four compounds—1-monopalmitin, isobutyl octyl oxalate, pentadecanoic acid, and dimethyl azelate—significantly inhibited Aβ42 aggregation. Additionally, isobutyl octyl oxalate and pentadecanoic acid disaggregated preformed Aβ42 aggregates. Fourth, molecular dynamics simulations were performed to examine the short-timescale behavior of the candidate compounds with the Aβ17–42 dimer, showing transient ligand–Aβ interactions associated with structural rearrangements at the dimer interface. Pharmacokinetic predictions supported drug-likeness, showing blood-brain barrier permeability and systemic clearance. Collectively, these findings identify four Jowiseungchungtang (JWS)-derived candidate compounds with Aβ aggregation-inhibitory activity and provide a mechanistic and pharmacokinetic basis for further development of these compounds as potential therapeutic agents in AD.
SN - 1482-1826
ER -