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Inquire: Software for real-time analysis of binding

查询：实时分析结合的软件

基本信息

批准号：
BB/K016601/1
负责人：
Adrian Mulholland
金额：
$ 13.47万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK016601%2F1
关键词：
Inquire Software real time analysis

项目摘要

Recent breakthroughs in hardware and software development allow computer simulations of biological molecules to reach timescales during which interesting biochemical events, such as protein folding, and drug binding and unbinding occur. This allows simulation to be used as a "computational microscope" to zoom in and watch the interactions of biomolecules such as proteins. For example, we have been using molecular dynamics simulations to watch the binding and unbinding of the flu drug Tamiflu(R) to its target protein, called neuraminidase. Using simulation, we can watch Tamiflu(R) unbinding from mutated forms of neuraminidase which we know come from mutants of flu that are drug-resistant, and for which Tamiflu(R) is no-longer an effective treatment. This is allowing us to build a computational assay, which lets us predict which mutations are likely to lead to drug resistance. However, while we can use our computational microscope to watch the drug unbind, merely watching something happen does not give us understanding of why it happens. To enable medicinal drug designers to develop new, mutation-resistant drugs, we need to be able to use computer simulation to gain understanding of the exact chemical details of the molecular interactions between the drug and the protein, and to quantify how those interactions change upon mutation. We have developed new, prototype software that is capable of this task. It is able to quantify the strength of attraction between a drug and a protein, and to quantify the attraction in terms of specific molecular interactions between the drug and individual parts of the protein, and individual water molecules around the drug binding site. We propose to develop and optimise our software, and to also build an intuitive, easy-to-use graphical interface, that will allow drug designers to easily perform this analysis in near-real time on a molecular dynamics trajectory. This will allow drug designers, molecular simulators, and anyone interested in molecular association, to gain an immediate, intuitive understanding of the molecular-scale driving forces to binding. This will aid medicinal researchers in the development of new drugs, and will aid researchers in their quest to understand how mutations in viruses and bacteria can lead to a loss of efficacy of existing drugs.

最近在硬件和软件开发方面的突破使计算机模拟生物分子达到了有趣的生化事件发生的时间尺度，如蛋白质折叠、药物结合和解除结合。这使得模拟可以用作“计算显微镜”来放大和观察生物分子（如蛋白质）的相互作用。例如，我们一直在使用分子动力学模拟来观察流感药物达菲（Tamiflu， R）与其靶蛋白（称为神经氨酸酶）的结合和解结合。通过模拟，我们可以观察到达菲(R)与神经氨酸酶突变形式的分离，我们知道这些神经氨酸酶突变形式来自具有耐药性的流感突变，而达菲(R)不再是一种有效的治疗方法。这使我们能够建立一个计算分析，让我们预测哪些突变可能导致耐药性。然而，虽然我们可以用计算机显微镜观察药物解绑定，但仅仅观察某些事情的发生并不能让我们理解它发生的原因。为了使药物设计人员能够开发新的抗突变药物，我们需要能够使用计算机模拟来了解药物和蛋白质之间分子相互作用的确切化学细节，并量化这些相互作用在突变时是如何变化的。我们已经开发出能够完成这项任务的新型原型软件。它能够量化药物和蛋白质之间的吸引力强度，并根据药物和蛋白质单个部分之间的特定分子相互作用以及药物结合位点周围的单个水分子来量化吸引力。我们建议开发和优化我们的软件，并建立一个直观，易于使用的图形界面，这将允许药物设计人员轻松地在分子动力学轨迹上进行近乎实时的分析。这将使药物设计人员、分子模拟器和任何对分子关联感兴趣的人能够立即、直观地了解分子尺度上的结合驱动力。这将有助于医学研究人员开发新药，并将有助于研究人员了解病毒和细菌的突变如何导致现有药物的功效丧失。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Entropy of Simulated Liquids Using Multiscale Cell Correlation.

DOI：
10.3390/e21080750
发表时间：
2019-07-31
期刊：
Entropy (Basel, Switzerland)
影响因子：
0
作者：
Ali HS;Higham J;Henchman RH
通讯作者：
Henchman RH

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

DOI：
10.1021/acs.jctc.1c00547
发表时间：
2021-10-12
期刊：
Journal of chemical theory and computation
影响因子：
5.5
作者：
Ansell TB;Curran L;Horrell MR;Pipatpolkai T;Letham SC;Song W;Siebold C;Stansfeld PJ;Sansom MSP;Corey RA
通讯作者：
Corey RA

New methods: general discussion.

新方法：一般性讨论。