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Drug Discovery


Figure 1: A representation of native MS data typically observed for a large, oligomeric protein complex. The accurate mass obtained defines the oligomeric state and stoichiometry of non-covalent complexes. Activation of complexes, for example by collision-induced dissociation, allows complexes to be dissociated into their constitute components, providing further details of composition. Small molecule binding with ligands such as lipids, substrates and drugs represent discrete increases in mass (adducts). The information obtained from high-resolution mass data is complementary to many other biophysical techniques, such as x-ray crystallography and electron microscopy, allowing for instance unknown electron densities to be attributed to specific molecules observed in native MS. Taken from Oxford Mass Technologies: Thermo Fisher Scientific Case Study ‘Driving Native Mass Spectrometry of Membrane Proteins for Pharmaceutical Research’ (CS72645 https://assets.thermofisher.com/TFS-Assets/CMD/Reference-Materials/cs-72645-native-ms-protein-characterization-omass-cs72645-en.pdf)


The exceptional power offered by Orbitrap™-


based instruments is leading the way when it comes to high mass, high resolution analysis. The latest Orbitrap™ instruments cover an ‘ultra-high’ mass range of up to 80,000 Da, with quadrupole mass selection up to 25,000 Da and pseudo-MS3 frag- mentation. Such advances in MS technology have also liber-


ated drug discovery scientists to explore the cou- pling of traditionally non-MS friendly separation techniques such as ion exchange chromatography (IEX) and size exclusion chromatography (SEC) with MS. Historically the coupling of these tech-


Drug Discovery World Summer 2018


niques was only possible via offline LC separations from which fractions were collected for subsequent static nanospray HRAM MS analysis. Through the direct combination of native protein chromato- graphic separations and HRAM detection, researchers now have at their disposal the possibil- ity of automated, high-throughput native intact mass analysis of complex therapeutics and drug targets/complexes.


Removing the analytical bottleneck While advances in mass range and resolution are generating ever more powerful insights, sample


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