標題: A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors
作者: 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
交大名義發表
生物科技學系
生物資訊及系統生物研究所
應用化學系
National Chiao Tung University
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
Department of Applied Chemistry
公開日期: 29-Jun-2020
摘要: 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 IC50 value of 2.7, 4.2, and 5.3 mu M, respectively. All three inhibitors significantly decrease LPS-induced TNF-alpha 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.
URI: http://dx.doi.org/10.1038/s41598-020-67420-9
http://hdl.handle.net/11536/154885
ISSN: 2045-2322
DOI: 10.1038/s41598-020-67420-9
期刊: SCIENTIFIC REPORTS
Volume: 10
Issue: 1
起始頁: 0
結束頁: 0
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