NMR imaging for the accelerated discovery of drugs and materials

现代科学以高效和信息量丰富的分析方法为基础。在过去的50年里，核磁共振波谱已经成为化学和生物研究中的主要分析技术之一。核磁共振提供了关于分子结构及其相互作用的丰富的原子级信息，这是使用其他技术无法获得的。核磁共振对于发现新的药物、材料和工业过程至关重要，大多数主要的研究机构都配备了核磁共振设施。核磁共振设备的高昂采购和维护成本，以及这项技术的广泛应用，意味着在核磁共振波谱仪上的时间是一种宝贵的资源。然而，尽管在自动化方面有了很大的进步，但许多涉及核磁共振的常见程序在光谱仪时间、劳动力和样本量方面都非常苛刻。这些要求是因为随着样品条件的调整(例如，pH、盐浓度、温度、溶剂组成)，经常需要对化学体系进行多次核磁共振测量。例如，测量药物化合物的pKa值(酸度)需要收集作为溶液pH函数的多组核磁共振光谱。通常，每个光谱必须单独记录，并且在连续的核磁共振实验之间手动调整溶液的pH值。即使是测量一种化合物的这种重要性质，也需要数小时的仪器和分析时间。药物输送系统的温度或pH响应性材料的开发也提出了类似的要求。在这个项目中，我将创建一个全新的核磁共振方法家族，它将允许在单个样品的单个实验中以传统方法的一小部分时间和成本来全面表征分子体系。我的技术是基于核磁共振成像(核磁共振-I)，与磁共振成像(MRI)相关。核磁共振-I结合了核磁共振提供的局部分析和核磁共振提供的丰富的化学信息。如今，几乎所有的核磁共振设备都可以在不加修改的情况下进行核磁共振-I，因此大多数研究人员都可以使用。通过改变样品中的条件并应用核磁共振-I，只需一次实验就可以对作为样品条件函数的系统进行全面分析。初步工作表明，使用我的方法，可以收集候选药物分子的90个单独的核磁共振光谱作为pH的函数，而使用传统方法在单个pH值下收集甚至一个光谱所需的时间。因此，核磁共振-I将加快新化学系统的开发和优化，同时解放研究人员从事其他工作。然而，有一些重大的挑战必须克服：首先，我需要开发在标准核磁共振样品管中创建和分析溶液性质的受控梯度的方法。这既是理论上的挑战，也是实验上的挑战，因为以前在该领域所做的工作很少。然而，一旦完成，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性质。与一家工业合作伙伴合作，我的方法将被应用于他们的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材料的新型刺激反应特性，如凝胶(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)。例如，可以找到药物从粘合剂或DNA折叠链中释放的临界条件。使用传统方法研究这些微妙的系统尤其困难。

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.