Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing
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...
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doaj-a74c1baa9c70470096d06839293e21142021-08-26T13:53:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-01229067906710.3390/ijms22169067Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug RepurposingJisu Oh0Hyeon Hae Lee1Yunhui Jeong2Siyeong Yoon3Hyun-Ju An4Minjung Baek5Do Kyung Kim6Soonchul Lee7Division of Hemato-Oncology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363 Dongbaekjukjeon-daero, Giheung-gu, Yongin-si 16995, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaCHA Graduate School of Medicine, 120 Hyeryong-ro, Pocheon 11160, KoreaDepartment of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seong-nam 13496, KoreaInadequate 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 L1000CDS<sup>2</sup> 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.https://www.mdpi.com/1422-0067/22/16/9067in silicodrug repurposingnoncytotoxic concentrationellipticineangiogenesis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jisu Oh Hyeon Hae Lee Yunhui Jeong Siyeong Yoon Hyun-Ju An Minjung Baek Do Kyung Kim Soonchul Lee |
spellingShingle |
Jisu Oh Hyeon Hae Lee Yunhui Jeong Siyeong Yoon Hyun-Ju An Minjung Baek Do Kyung Kim Soonchul Lee Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing International Journal of Molecular Sciences in silico drug repurposing noncytotoxic concentration ellipticine angiogenesis |
author_facet |
Jisu Oh Hyeon Hae Lee Yunhui Jeong Siyeong Yoon Hyun-Ju An Minjung Baek Do Kyung Kim Soonchul Lee |
author_sort |
Jisu Oh |
title |
Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing |
title_short |
Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing |
title_full |
Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing |
title_fullStr |
Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing |
title_full_unstemmed |
Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing |
title_sort |
paradoxical pro-angiogenic effect of low-dose ellipticine identified by in silico drug repurposing |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-08-01 |
description |
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 L1000CDS<sup>2</sup> 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. |
topic |
in silico drug repurposing noncytotoxic concentration ellipticine angiogenesis |
url |
https://www.mdpi.com/1422-0067/22/16/9067 |
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