NMR imaging for the accelerated discovery of drugs and materials

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.

Nuclear magnetic resonance (NMR) spectroscopy is one of the main analytical techniques used in modern chemical and biological research. If it's a new drug, a new material or a cosmetic ingredient the chances are it has been inside an NMR spectrometer sometime during its development. In this project, I will work with partners in the pharmaceutical and scientific software industries to create a unique set of NMR imaging tools and software that can be used to study chemical systems as a function of the sample conditions with unprecedented efficiency. These tools will benefit greatly the many researchers in both industry and academia who use NMR routinely in their research. Specific beneficiaries of my research can be identified:

Industry:
The pharmaceutical industry is a particularly heavy user of NMR spectroscopy. Compounds identified as having therapeutic potential through computational searches are synthesised and their key properties measured by NMR, for example their ability to bind to a protein or their molecular shapes and charges. Such analysis usually involves tedious adjustment of the sample conditions between successive NMR experiments with the result that an entire morning of instrument and analyst time can be required to measure a key property of even a single compound; for example the drug acidity (pKa value). My NMR imaging techniques will enable a more informed drug design process, by allowing higher resolution data to be collected, while simultaneously increasing productivity by allowing more compounds to be analysed in a shorter period of time. The project will thus aid the development of the next generation of medicines to treat a range of diseases.

The high costs of conventional NMR methodologies are especially acute for small and medium-sized enterprises (SMEs) who often have to purchase time on the NMR equipment of other research institutions. In this project, I will develop my imaging methods with input and guidance from an SME involved in drug development, C4X Discovery (Manchester, UK). While the project will undoubtedly benefit from C4X's experience, it will also enhance C4X's position as a beacon of excellence for the discovery and development of small molecules to the pre-clinical stage.

I will develop my NMR imaging methods to be, from the outset, accessible and easy-to-use for non-specialists. To do this, I have enlisted the help of two leading scientific software companies as project partners: Mestrelab Research SL and Software 4 Science Developments. Once my NMR imaging methods have been validated and are better known among the scientific community, my data processing methods will be incorporated into formal software tools available as plugins for the software produced by these companies. Overall, my project will enhance the knowledge base in scientific software for NMR data processing/fitting and encourage further innovations in this fast-moving field. Improvements in scientific software will, in turn, enable increased productivity and insight both in academia and industry. The project will also promote the sharing of ideas and experiences between all three companies, which will likely deliver further innovations aside from the project.

Public engagement:
Analytical science makes a largely 'invisible' contribution to modern scientific advances. Analytical science is, in turn, underpinned by seemingly abstract topics such as diffusion mathematics which is used extensively in this project to control the sample conditions. I plan to run events at the Norwich Science Festival where the public will be invited to use simple diffusion equations to establish diffusion gradients of food dyes and simultaneously learn about the work of my team on the high-throughput characterisation of pharmaceutical ingredients, biomaterials and proteins. I also plan to host undergraduate summer project students in the lab to inspire them to follow careers in scientific research.