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.