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Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing

Authors
 Jisu Oh  ;  Hyeon Hae Lee  ;  Yunhui Jeong  ;  Siyeong Yoon  ;  Hyun-Ju An  ;  Minjung Baek  ;  Do Kyung Kim  ;  Soonchul Lee 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.22(16) : 9067, 2021-08 
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
 1661-6596 
Issue Date
2021-08
Keywords
angiogenesis ; drug repurposing ; ellipticine ; in silico ; noncytotoxic concentration
Abstract
Inadequate vessel maintenance or growth causes ischemia in diseases such as myocardial infarction, stroke, and neurodegenerative disorders. Therefore, developing an effective strategy to salvage ischemic tissues using a novel compound is urgent. Drug repurposing has become a widely used method that can make drug discovery more efficient and less expensive. Additionally, computational virtual screening tools make drug discovery faster and more accurate. This study found a novel drug candidate for pro-angiogenesis by in silico virtual screening. Using Gene Expression Omnibus (GEO) microarray datasets related to angiogenesis studies, differentially expressed genes were identified and characteristic direction signatures extracted from GEO2EnrichR were used as input data on L1000CDS2 to screen pro-angiogenic molecules. After a thorough review of the candidates, a list of compounds structurally similar to TWS-119 was generated using ChemMine Tools and its clustering toolbox. ChemMine Tools and ChemminR structural similarity search tools for small-molecule analysis and clustering were used for second screening. A molecular docking simulation was conducted using AutoDock v.4 to evaluate the physicochemical effect of secondary-screened chemicals. A cell viability or toxicity test was performed to determine the proper dose of the final candidate, ellipticine. As a result, we found ellipticine, which has pro-angiogenic effects, using virtual computational methods. The noncytotoxic concentration of ellipticine was 156.25 nM. The phosphorylation of glycogen synthase kinase-3β was decreased, whereas the β-catenin expression was increased in human endothelial cells treated with ellipticine. We concluded that ellipticine at sublethal dosage could be successfully repositioned as a pro-angiogenic substance by in silico virtual screening.
Files in This Item:
T202103672.pdf Download
DOI
10.3390/ijms22169067
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Oh, Jisu(오지수)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184789
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