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摘要
目前在设计和表征药物时的努力往往依赖于他们的蛋白质目标结构。然而,有很大一部分的蛋白质缺乏独特的三维结构,并存在高度动态的结构组装。这些本质上无序的蛋白质参与各种人类疾病的发病机制,并在真核生物中是非常丰富的。综合分析当前药物人类蛋白质组覆盖的12类药物和18大类药物靶向,我们展示了高结构覆盖和内在无序的显著偏差。我们回顾了这种偏见的原因,包括广泛使用的不同阶段的药物开发和表征过程以及难以得到结构的内在无序蛋白质的信息。我们还讨论了将未来的本质无序的蛋白质作为药物靶标。鉴于人类蛋白质整体的高度无序以及当前针对结构蛋白可用药物的人类蛋白质组的偏差,无序蛋白质组会增加一系列的有前景的药物靶标是不可避免的。蛋白质无序的辅助药物设计可以从目前的合理的药物设计技术中描绘,也需要新的方法,从而不再依赖于一个独特的蛋白质结构。
关键词: 障碍疾病;药物蛋白组学;内在的障碍;固有无序蛋;人类药物的目标;合理的药物设计。
Current Drug Targets
Title:Untapped Potential of Disordered Proteins in Current Druggable Human Proteome
Volume: 17 Issue: 10
Author(s): Gang Hu, Zhonghua Wu, Kui Wang, Vladimir N. Uversky, Lukasz Kurgan
Affiliation:
关键词: 障碍疾病;药物蛋白组学;内在的障碍;固有无序蛋;人类药物的目标;合理的药物设计。
摘要: Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However, a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes. Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder. We review reasons for this bias including widespread use of the structural information in various stages of drug development and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein structure.
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Cite this article as:
Gang Hu, Zhonghua Wu, Kui Wang, Vladimir N. Uversky, Lukasz Kurgan , Untapped Potential of Disordered Proteins in Current Druggable Human Proteome, Current Drug Targets 2016; 17 (10) . https://dx.doi.org/10.2174/1389450116666150722141119
DOI https://dx.doi.org/10.2174/1389450116666150722141119 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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