NMR imaging for the accelerated discovery of drugs and materials

Analytical methods play a vital but often hidden role in scientific research. Nuclear magnetic resonance (NMR) spectroscopy is an indispensable technique for probing the structure of molecules at the atomic level and underpins modern drug discovery, industrial process research and studies of biological systems. Most large research institutions have NMR facilities while advances in spectrometer design and automation make the technique fully accessible to non-specialist researchers. Nevertheless, the high purchase and maintenance costs of NMR equipment make time on an NMR spectrometer a precious resource. In the initial period of this project, my team have devised fundamentally new ways of using common equipment that greatly enhance the quantity of information afforded by NMR analysis while shrinking the time and reducing the quantity of sample required. Through innovative experiment design, we can vary the conditions of a sample (pH, solvent composition, molecular concentration) using concentration gradients and interrogate the system using NMR imaging (NMR-I), a 1D variant of magnetic resonance imaging (MRI). By avoiding manual adjustment of the sample conditions, our approach reduces the time required to characterise a chemical system from hours to minutes and enables measurements to be performed that would be unfeasible via conventional approaches. So far, we have demonstrated the rapid assessment of how strongly calcium and magnesium ions bind to food additives (DOI: 10.1021/acs.analchem.2c01166) and how a drug molecule binds to a target protein (DOI: 10.1021/jacs.3c02218). We have also demonstrated the measurement of pH (acidity) in any mixture of solvents, removing the need for cumbersome calibration experiments and liberating experimenters to perform accurate measurements under the exact conditions demanded by their research (DOI: 10.1021/acs.analchem.3c02771). In the later period of this project, we will apply and further develop our methodologies by tackling current problems in biomass processing, microbiology, drug discovery, digestive health and the study of complex molecules such as DNA and enzymes. Four complementary objectives will be pursued, each presenting significant challenges that will require collaboration with partners across other disciplines: Firstly, we will develop a set of tools to identify unknown molecules present in highly complex mixtures. The drive towards sustainable production of products such as pharmaceutical materials has led to the increased use of biomass sources. However, these extracts contain an incredible diversity of molecules, from valuable trace nutrients such as zinc through to large polymers. Identification of these molecules is required for optimisation of extraction processes to maximise yields and minimise waste. The tools we have developed will allow us to identify the functional groups present on the molecules, thus facilitating identification of useful products in biomass extracts and revealing the molecular workings of microorganisms. Secondly, building on our pioneering methods to determine the acidity and protein binding characteristics of model drugs, we will eliminate drawbacks that have emerged during testing of our methodologies with partners in the pharmaceutical industry and further enhance the information afforded in the quest for new drugs. Thirdly, we will develop models of the human gut within standard NMR sample tubes to allow digestive processes to be monitored in real-time, providing a new tool to test fortified foodstuffs. Finally, we will create a new set of tools to evaluate the optimum conditions and rates of activity of enzymes, with potential applications ranging from biotechnology to element cycling within the oceans. We will also explore how the same approach can be used to tailor the rate of formation and properties of DNA secondary structures and self-assembling materials for applications in photovoltaics and wearable electronics.