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A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors
The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324578/ https://www.ncbi.nlm.nih.gov/pubmed/32601404 http://dx.doi.org/10.1038/s41598-020-67420-9 |
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author | Hsu, Kai-Cheng HuangFu, Wei-Chun Lin, Tony Eight Chao, Min-Wu Sung, Tzu-Ying Chen, Yi-Ying Pan, Shiow-Lin Lee, Jih-Chin Tzou, Shey-Cherng Sun, Chung-Ming Yang, Jinn-Moon |
author_facet | Hsu, Kai-Cheng HuangFu, Wei-Chun Lin, Tony Eight Chao, Min-Wu Sung, Tzu-Ying Chen, Yi-Ying Pan, Shiow-Lin Lee, Jih-Chin Tzou, Shey-Cherng Sun, Chung-Ming Yang, Jinn-Moon |
author_sort | Hsu, Kai-Cheng |
collection | PubMed |
description | The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC(50) value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs. |
format | Online Article Text |
id | pubmed-7324578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73245782020-07-01 A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors Hsu, Kai-Cheng HuangFu, Wei-Chun Lin, Tony Eight Chao, Min-Wu Sung, Tzu-Ying Chen, Yi-Ying Pan, Shiow-Lin Lee, Jih-Chin Tzou, Shey-Cherng Sun, Chung-Ming Yang, Jinn-Moon Sci Rep Article The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC(50) value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs. Nature Publishing Group UK 2020-06-29 /pmc/articles/PMC7324578/ /pubmed/32601404 http://dx.doi.org/10.1038/s41598-020-67420-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Hsu, Kai-Cheng HuangFu, Wei-Chun Lin, Tony Eight Chao, Min-Wu Sung, Tzu-Ying Chen, Yi-Ying Pan, Shiow-Lin Lee, Jih-Chin Tzou, Shey-Cherng Sun, Chung-Ming Yang, Jinn-Moon A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title | A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title_full | A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title_fullStr | A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title_full_unstemmed | A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title_short | A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors |
title_sort | site-moiety map and virtual screening approach for discovery of novel 5-lox inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324578/ https://www.ncbi.nlm.nih.gov/pubmed/32601404 http://dx.doi.org/10.1038/s41598-020-67420-9 |
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