Native mass spectrometry (native MS) relies on non-denaturing electrospray- ionization (ESI) to recognize multi-charged proteins in their near-native states. It is a label-free, fast, and accurate method that permits the direct observation of non-covalent and covalent protein-ligand complexes. Collision induced affinity selection mass spectrometry (CIAS-MS) is a method developed by the group to identify a ligand binding to proteins. Whereas native MS detects protein-ligand complexes, CIAS-MS only detects bound ligand(s). The advantage of this method is that it does not require the protein to be visible under MS conditions. This is particularly useful for studying challenging proteins which have poor visibility under native MS conditions, such as membrane proteins, as well as complex protein mixtures such as cell lysates.
Over the last 5 years, our group has advanced the application of native MS and CIAS-MS from measuring binding interactions of individual small molecules (ligands) with proteins in their native state, to screening libraries of compounds and compound mixtures, to protein mixtures, membrane proteins, and ternary protein-ligand-protein molecular glue type complexes. Our outcomes which involved collaborations with disease experts in academia and industry include identification of new cancer, malaria, neurodegenerative diseases, tuberculosis and COVID-19 therapeutic candidates.
The current focus lies on further refining our platform to probe increasingly complex mixtures of proteins using known small molecule drugs and bioactive compounds identified from phenotypic assays where the target protein is unknown. The ultimate aim is to precisely and directly identify the target protein for every small molecule drug candidate within disease-relevant cell lysates. This ongoing development holds immense promise for advancing drug discovery and understanding disease mechanisms.