摘要
变构效应是一个长期的内部调节的分子机制,在变构位点的配体结合在蛋白的远端部分诱导产生构象变化,从而修饰其活性。从药物设计的观点出发,因为结合变构位点的配体能够用来调节靶蛋白,这种机制可以被利用来实现重要的治疗作用。从这个意义上来说,计算工具是有效的方法,因为他们允许在蛋白质的变构通讯的特性,这是设计调节配体的基础。然而,考虑到大分子长程相互作用的,对研究人员来说主要的药物设计工是分子动力学和相关的应用程序,因为它可以对绑定到配体的蛋白质的构象变化进行有效评价。特别是,全原子分子动力学可以用于确认内部机制,该机制可编排变构通讯,以识别关键残基和改变蛋白质的行为的内部途径。问题是,这些技术在很大程度上耗费时间和计算密集型的,因此需要高性能计算系统,包括并行计算和GPU加速计算,以实现在一定时间内取得结果。本文讨论了如何利用在硅片的方法来表征变构调制和蛋白质的长程相互作用,描述了热休克蛋白的案例研究,热休克蛋白是一类由应力条件下调节的伴侣,因其涉及许多癌症和神经退行性疾病而显得十分重要。
关键词: Allostery
图形摘要
Current Drug Targets
Title:HPC Analysis of Multiple Binding Sites Communication and Allosteric Modulations in Drug Design: The HSP Case Study
Volume: 17 Issue: 14
Author(s): Federica Chiappori, Luciano Milanesi, Ivan Merelli
Affiliation:
关键词: Allostery
摘要: Allostery is a long-range macromolecular mechanism of internal regulation, in which the binding of a ligand in an allosteric site induces distant conformational changes in a distant portion of the protein, modifying its activity. From the drug design point of view, this mechanism can be exploited to achieve important therapeutic effects, since ligands able to bind allosteric sites may be designed to regulate target proteins. Computational tools are a valid support in this sense, since they allow the characterization of allosteric communications within proteins, which are essential to design modulator ligands. While considering long-range interactions in macromolecules, the principal drug design tool available to researcher is molecular dynamics, and related applications, since it allows the evaluation of conformational changes of a protein bound to a ligand. In particular, all-atoms molecular dynamics is suitable to verify the internal mechanisms that orchestrate allosteric communications, in order to identify key residues and internal pathways that modify the protein behaviour. The problem is that these techniques are heavily time-consuming and computationally intensive, thus high performance computing systems, including parallel computing and GPU-accelerated computations, are necessary to achieve results in a reasonable time. In this review, we will discuss how it is possible to exploit in silico approaches to characterize allosteric modulations and long-range interactions within proteins, describing the case study of the Heat Shock Proteins, a class of chaperons regulated by stress conditions, which is particularly important since it is involved in many cancers and neurodegenerative diseases.
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Cite this article as:
Federica Chiappori, Luciano Milanesi, Ivan Merelli , HPC Analysis of Multiple Binding Sites Communication and Allosteric Modulations in Drug Design: The HSP Case Study, Current Drug Targets 2016; 17 (14) . https://dx.doi.org/10.2174/1389450117666151209123646
DOI https://dx.doi.org/10.2174/1389450117666151209123646 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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