摘要
背景:细胞周期蛋白依赖性激酶(CDK)包含用于开发药物的重要蛋白质家族,主要用于治疗癌症,但也有用于发展神经变性疾病和糖尿病的药物。自20世纪90年代初以来,对CDKs进行了结构研究,以确定抑制该蛋白质靶标的结构基础。 目标:我们的目标是回顾近期关于CDK的结构性研究。我们专注于了解抑制CDK,结构和配体结合信息的结构基础的最新发展。 方法:蛋白质晶体学已成功应用于阐明400多种CDK结构。这些结构中的大多数与抑制剂复合。我们使用这种丰富的结构信息来描述确定该酶的抑制的主要结构特征。 结果:已经阐明了CDK1,2,4-9,12,13和16的结构。与广泛的不同竞争性抑制剂复合的这些结构的分析强烈地表明可用于指导CDK抑制剂的发展的一些常见特征,例如氢键的形式和配体结构中卤素原子的存在。 结论:现在我们有数百个CDK的结构信息。结合结构和功能信息,我们可以说,分子间氢键的模式对抑制剂特异性至关重要。此外,机器学习技术在预测CDK的结合亲和力方面已经显示出改进。
关键词: 细胞周期蛋白依赖性激酶,结合亲和力,药物设计,机制学习,神经变性疾病,抑制剂
Current Drug Targets
Title:Understanding the Structural Basis for Inhibition of Cyclin-Dependent Kinases. New Pieces in the Molecular Puzzle
Volume: 18 Issue: 9
关键词: 细胞周期蛋白依赖性激酶,结合亲和力,药物设计,机制学习,神经变性疾病,抑制剂
摘要: Background: Cyclin-dependent kinases (CDKs) comprise an important protein family for development of drugs, mostly aimed for use in treatment of cancer but there is also potential for development of drugs for neurodegenerative diseases and diabetes. Since the early 1990s, structural studies have been carried out on CDKs, in order to determine the structural basis for inhibition of this protein target.
Objective: Our goal here is to review recent structural studies focused on CDKs. We concentrate on latest developments in the understanding of the structural basis for inhibition of CDKs, relating structures and ligand-binding information. Method: Protein crystallography has been successfully applied to elucidate over 400 CDK structures. Most of these structures are complexed with inhibitors. We use this richness of structural information to describe the major structural features determining the inhibition of this enzyme. Results: Structures of CDK1, 2, 4-9, 12 13, and 16 have been elucidated. Analysis of these structures in complex with a wide range of different competitive inhibitors, strongly indicate some common features that can be used to guide the development of CDK inhibitors, such as a pattern of hydrogen bonding and the presence of halogen atoms in the ligand structure. Conclusion: Nowadays we have structural information for hundreds of CDKs. Combining the structural and functional information we may say that a pattern of intermolecular hydrogen bonds is of pivotal importance for inhibitor specificity. In addition, machine learning techniques have shown improvements in predicting binding affinity for CDKs.Export Options
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Cite this article as:
Understanding the Structural Basis for Inhibition of Cyclin-Dependent Kinases. New Pieces in the Molecular Puzzle, Current Drug Targets 2017; 18 (9) . https://dx.doi.org/10.2174/1389450118666161116130155
DOI https://dx.doi.org/10.2174/1389450118666161116130155 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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