The proposed research will develop a new analytical tool to support drug discovery. The tool, known as native liquid extraction surface analysis (NESA) mass spectrometry, combines two emerging mass spectrometry techniques, and has the potential to revolutionise the drug discovery pipeline by addressing a key challenge, namely the ability to make measurements in the full complexity of the biological environment.
Drug discovery is the process whereby new potential medicines are identified. Typically, drug discovery involves initial screening of a library of compounds against a particular 'target' (e.g., a protein that has previously been identified as being involved in a particular illness or disease). This initial screening results in hit compounds ('hits') which are then optimised to improve their performance. At this stage, the potential drug enters the pre-clinical phase of drug development in which its safety, toxicity, and metabolism are assessed prior to clinical trials.
The early stages of drug discovery are very much focused on optimising the interactions (known as non-covalent interactions) between the target and the potential drug. The aims are to improve the binding affinity, i.e., strengthen the interaction between the drug and the target, and to improve target selectivity, i.e., ensure the drug binds to one target only. These measurements, however, are made outside of the physiological context. There are two limitations to this isolationist approach. Firstly, disease states are the result of complex networks of molecular pathways, and the effectiveness of drug discovery is hampered by incomplete understanding of the response of those molecular pathways to the drug(s). The ability to measure interactions between the target and drug in the full biological context would transform this facet of drug discovery. Secondly, the safety and toxicological effects resulting from interaction of the drug with other molecules ("off-target" effects) cannot be assessed at this stage. The latter is particularly important when considering the very high attrition rate of drug development. The success rate for a drug entering clinical trials eventually making it to the market is less than 10%. The number one reason for failure at this stage is non-clinical toxicology. The ability to assess toxicological effects earlier in the drug discovery process would reduce attrition rates, and improve the efficiency of drug discovery and development.
Nevertheless, the ability to make analytical measurements in the physiological context is a major challenge for the physical sciences, and this work seeks to address that challenge. The aim is to develop an analytical chemistry technique - NESA mass spectrometry - for the characterisation of interactions between protein targets and drug compounds directly from complex biological environments, including blood, tissue and cells. Broadly, mass spectrometry is an analytical technique which offers high sensitivity, broad specificity (all molecules have a mass), and the capability for molecular structure elucidation. Two emerging mass spectrometry approaches are native mass spectrometry, which preserves non-covalent interactions such as those between protein targets and drugs thus allowing their interrogation, and liquid extraction surface analysis, which allows sampling of molecules directly from their actual environment. The research described in this proposal will couple these exciting techniques and apply them to the challenge of characterisation of protein - drug interactions in the full biological context.
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