Native MS in Drug Discovery & Development

In this month’s blog post, we’re spotlighting one of our newest service lines – Native MS. This powerful technology is available as a follow-up to our ASMS non-covalent binding assays but can also be performed as part of any other research workflow, or as a stand-alone experiment. By leveraging this approach to analyze protein-protein and protein-ligand complexes, researchers can gain valuable insights into the structure and properties of biomolecules in their native state. The addition of this service line further bolsters Momentum’s commitment to leveraging the analytical power of mass spectrometry towards a broad range of drug discovery and development applications and represents an exciting addition to our service catalog. Read on to learn more about what Native MS is and how this technology can benefit your research program!

What is Native MS?

Native MS, or native mass spectrometry, is a mass spectrometry technique for the quantitative analysis and characterization of intact proteins, protein-protein complexes, and protein-ligand complexes. Critically, these entities remain in a native-like conformation during the analysis process, with non-covalent interactions faithfully preserved. Analysis conditions are specially designed to maintain interactions between complex subunits, as well as interactions between protein targets and non-covalent binders. As a result, researchers can gain unique insights into higher-level complex structure, subunit stoichiometry, post-translational modifications, and other key parameters. Native MS offers a powerful methodology to analyze proteins, complexes, and protein-ligand interactions under near-endogenous conditions, and the information obtained can be used to inform a broad range of drug discovery and development efforts.

How is Native MS different from traditional MS?

Both Native MS and traditional mass spectrometry involve the quantitative identification and analysis of ionized samples on the basis of their mass-to-charge ratios. In the context of drug discovery and development efforts, these techniques can be applied for a variety of applications, including to identify relevant proteins or compounds, quantify protein abundance across samples, and characterize drug-target interactions. In traditional mass spectrometry, samples are subjected to denaturing conditions during the preparation and ionization process. This means that any non-covalent bonds present in the input sample are disrupted, leading to the dissociation of complex subunits and non-covalent ligands. In contrast, Native MS is performed using specialized sample preparation and analysis conditions that are designed to preserve non-covalent interactions. As a result, multi-protein complexes and drug-bound targets can be analyzed in their intact form, and the resulting data more accurately reflects how these targets behave and interact in an endogenous context.

How is Native MS used for drug discovery and development?

Native MS enables researchers to probe the native configuration of a target protein (with or without associated subunits and bound ligands). As a result, this approach can provide a wealth of structural and functional insights relevant to drug discovery and development research. In the early stages of target selection and characterization, it can be used to evaluate a target’s native conformation, either alone or as part of a multi-subunit complex. This information can be used to identify potential binding interfaces and otherwise guide structure-based drug discovery efforts.

Once a lead molecule has been discovered, Native MS can be used to identify binding sites on the target protein and detect conformational changes induced by ligand binding. The assay can also be used to quantify binding interactions, including determination of K_d values, stoichiometry, and kinetic properties. In the development of targeted protein degraders, molecular glue degraders, and protein-protein interaction (PPI) modulators, Native MS provides a powerful methodology to monitor ternary complex formation or PPI induction/disruption. This technique can also be applied towards other specialized drug development efforts, such as for the characterization of antibodies and antibody-drug complexes, analysis of amyloid plaque formation, and evaluation of AAVs and other viral capsids.

If you’re interested in learning more about how Native MS can provide valuable insights to advance your drug discovery and development research, send us a message and get connected to our scientific team.

 

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