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.
Export Options
About this article
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 |
Related Journals
Related Books
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Meet Our Editorial Board Member
Current Psychiatry Reviews Autoantibodies Profile in Matching CSF and Serum from AD and aMCI patients: Potential Pathogenic Role and Link to Oxidative Damage
Current Alzheimer Research Recent Advancement of Pyrazole Scaffold Based Neuroprotective Agents: A Review
CNS & Neurological Disorders - Drug Targets Isoprostanes as Biomarkers and Mediators of Oxidative Injury in Infant and Adult Central Nervous System Diseases
Current Neurovascular Research Nano Phytomedicine Based Delivery System for CNS Disease
Current Drug Metabolism Vitamin E - Occurrence, Biosynthesis by Plants and Functions in Human Nutrition
Mini-Reviews in Medicinal Chemistry Amyloid β Oligomers Decrease Hippocampal Spontaneous Network Activity in an Age-Dependent Manner
Current Alzheimer Research Nanotechnology Driven Approaches for the Management of Parkinson’s Disease: Current Status and Future Perspectives
Current Drug Metabolism Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease
Recent Patents on Anti-Cancer Drug Discovery Behavioral Experimental Paradigms for the Evaluation of Drug’s Influence on Cognitive Functions: Interpretation of Associative, Spatial/Nonspatial and Working Memory
CNS & Neurological Disorders - Drug Targets Protein Folding, Misfolding and Aggregation: Evolving Concepts and Conformational Diseases
Protein & Peptide Letters Brain-Derived Neurotrophic Factor (BDNF) has Proliferative Effects on Neural Stem Cells through the Truncated TRK-B Receptor, MAP Kinase, AKT, and STAT-3 Signaling Pathways
Current Neurovascular Research Peptide Inhibitors Targeting Protein Kinases
Current Pharmaceutical Design Functional Multipotency of Stem Cells: A Conceptual Review of Neurotrophic Factor-Based Evidence and Its Role in Translational Research
Current Neuropharmacology Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors: A Review
Current Topics in Medicinal Chemistry Withania somnifera Phytochemicals Confer Neuroprotection by Inhibition of the Catalytic Domain of Human Matrix Metalloproteinase-9
Letters in Drug Design & Discovery Structure and Comparative Analysis of the Bovine Prion Gene Locus
Current Genomics A New Drug Candidate (GEMSP) for Multiple Sclerosis
Current Medicinal Chemistry Pluripotent Stem Cell-Derived Somatic Stem Cells as Tool to Study the Role of MicroRNAs in Early Human Neural Development
Current Molecular Medicine Neurochemistry Changes Associated with Mutations in Familial Parkinsons Disease
Current Medicinal Chemistry