NMR imaging for the accelerated discovery of drugs and materials

核磁共振成像加速药物和材料的发现

• 批准号: MR/T044020/1
• 负责人: Matthew Wallace
• 金额: $ 154.47万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT044020%2F1
• 关键词: NMR; imaging; accelerated; discovery; drugs

Modern science is underpinned by efficient and informative analytical methods. Over the past 50 years, nuclear magnetic resonance (NMR) spectroscopy has grown to be one of the dominant analytical techniques in chemical and biological research. A wealth of atomic level information is afforded by NMR on the structure of molecules and their interactions that is inaccessible using other techniques. NMR is vital for the discovery of new drugs, materials and industrial processes and most major research institutions are equipped with NMR facilities.The high purchase and maintenance costs of NMR equipment, along with the widespread utility of the technique, mean that time on an NMR spectrometer is a precious resource. Nevertheless, despite considerable advances in automation, many common procedures involving NMR are extremely demanding in terms of spectrometer time, labour and sample quantity. These demands arise from the frequent requirement to perform multiple NMR measurements on chemical systems as the sample conditions are adjusted (e.g. pH, salt concentration, temperature, solvent composition). For example, the measurement of the pKa value (acidity) of a drug compound requires sets of NMR spectra to be collected as a function of the solution pH. Conventionally, each spectrum must be recorded separately and the pH of the solution adjusted manually between successive NMR experiments. Hours of instrument and analyst time are required to measure this vital property of even a single compound. Similar demands are imposed by the development of temperature or pH-responsive materials for drug delivery systems. The high cost of conventional NMR analysis thus presents a significant barrier to the development of new drugs and materials.In this project, I will create a whole new family of NMR methodologies that will allow the full characterisation of molecular systems in single experiments on single samples with a fraction of the time and cost of conventional approaches. My techniques are based upon NMR imaging (NMR-I), a relative of magnetic resonance imaging (MRI). NMR-I combines the localised analysis afforded by MRI with the wealth of chemical information afforded by NMR. NMR-I can nowadays be performed on almost all NMR equipment without modification and is thus accessible to the majority of researchers. By varying the conditions within a sample and applying NMR-I, it will be possible to perform a full analysis of a system as a function of the sample conditions in just a single experiment. Initial work has shown how, using my methods, 90 individual NMR spectra of a candidate drug molecule can be collected as a function of pH in the time it would take to collect even a single spectrum at a single pH value using conventional approaches. NMR-I will thus accelerate the development and optimisation of new chemical systems while simultaneously freeing up researchers for other duties. There are, however, significant challenges that must be overcome:Firstly, I need to develop ways of creating and analysing controlled gradients of solution properties in standard NMR sample tubes. This is both a theoretical and experimental challenge as little prior work has been done in the field. However, once completed it will be possible to measure the key properties of small molecules, including pharmaceuticals, with unprecedented efficiency. Working with an industrial partner, my methods will be applied to the high-throughput characterisation of compounds in their drug discovery pipeline. Secondly, I will develop techniques that grant researchers access to the novel stimuli-responsive properties of materials such as gels (drug delivery systems, foods, personal care) and polymer electrolytes (DNA, gene vectors, nanotechnology). For example, it will be possible to find the critical conditions at which a drug is released from a binder or a strand of DNA folds. These delicate systems are especially difficult to study using conventional approaches.

现代科学以有效和信息丰富的分析方法为基础。在过去的50年里，核磁共振（NMR）光谱已发展成为化学和生物研究中的主要分析技术之一。核磁共振提供了大量的原子水平的信息，这些信息是使用其他技术无法获得的。核磁共振对于新药、新材料和新工艺的发现至关重要，大多数主要研究机构都配备了核磁共振设备。核磁共振设备的高昂购买和维护成本以及该技术的广泛应用沿着，意味着核磁共振波谱仪上的时间是一种宝贵的资源。然而，尽管在自动化方面取得了相当大的进步，但涉及NMR的许多常见程序在光谱仪时间、劳动力和样品量方面都要求极高。这些需求来自于在调整样品条件（例如pH、盐浓度、温度、溶剂组成）时对化学系统进行多次NMR测量的频繁要求。例如，药物化合物的pKa值（酸度）的测量需要收集作为溶液pH值的函数的NMR光谱集。通常，必须单独记录每个光谱，并在连续的NMR实验之间手动调节溶液的pH值。即使是测量一种化合物的这一重要性质，也需要数小时的仪器和分析时间。通过开发用于药物递送系统的温度或pH响应性材料也提出了类似的要求。因此，传统NMR分析的高成本对新药和新材料的开发构成了重大障碍。在本项目中，我将创建一个全新的NMR方法家族，该方法将允许在单个样品的单个实验中对分子系统进行全面表征，而传统方法的时间和成本仅为一小部分。我的技术是基于核磁共振成像（NMR-I），一个相对的磁共振成像（MRI）。NMR-I将MRI提供的局部分析与NMR提供的丰富化学信息相结合。NMR-I现在可以在几乎所有的NMR设备上进行，无需修改，因此大多数研究人员都可以使用。通过改变样品内的条件并应用NMR-1，将有可能仅在单个实验中根据样品条件对系统进行全面分析。最初的工作已经表明，使用我的方法，可以收集候选药物分子的90个单独的NMR光谱作为pH值的函数，在使用常规方法收集单个pH值下的单个光谱所需的时间内。因此，NMR-I将加速新化学系统的开发和优化，同时将研究人员从其他职责中解放出来。然而，必须克服的重大挑战是：首先，我需要开发在标准NMR样品管中创建和分析溶液性质的受控梯度的方法。这是一个理论和实验上的挑战，因为在该领域很少有先前的工作。然而，一旦完成，它将有可能以前所未有的效率测量包括药物在内的小分子的关键特性。与一个工业合作伙伴合作，我的方法将被应用于药物发现管道中化合物的高通量表征。其次，我将开发技术，使研究人员能够获得凝胶（药物输送系统，食品，个人护理）和聚合物电解质（DNA，基因载体，纳米技术）等材料的新型刺激响应特性。例如，将有可能找到药物从粘合剂或DNA折叠链中释放的临界条件。这些微妙的系统特别难以使用传统方法进行研究。

项目成果

Nuclear Magnetic Resonance - Volume 49

核磁共振 - 第 49 卷

• DOI: 10.1039/bk9781837672455-00177
• 发表时间: 2023
• 作者: Wallace M

Nuclear Magnetic Resonance - Volume 47

核磁共振 - 第 47 卷

• DOI: 10.1039/9781839164965-00183
• 发表时间: 2021
• 作者: Wallace M

Hierarchical Composite Self-Sorted Supramolecular Gel Noodles

• DOI: 10.1002/adma.202211277
• 发表时间: 2023-03-15
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Marshall, Libby J.;Wallace, Matthew;Adams, Dave J.
• 通讯作者: Adams, Dave J.

Imaging Saturation Transfer Difference (STD) NMR: Affinity and Specificity of Protein-Ligand Interactions from a Single NMR Sample.

• DOI: 10.1021/jacs.3c02218
• 发表时间: 2023-08-02
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Monaco, Serena;Angulo, Jesus;Wallace, Matthew
• 通讯作者: Wallace, Matthew

Nuclear Magnetic Resonance - Volume 48

核磁共振 - 第 48 卷

• DOI: 10.1039/9781839167690-00229
• 发表时间: 2022
• 作者: Wallace M