Structural highlights
FunctionPublication Abstract from PubMedHydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) is an established tool in drug discovery, used to characterize target engagement and conformational dynamics, and frequently used in both biopharmaceutical and small molecule drug discovery. Conventional HDX-MS experiments are performed at saturating ligand concentrations to generate a binding "footprint", where decreased solvent exchange reflects a local structural stabilization or reduced solvent accessibility upon binding. Here, we present an extended HDX-MS and HDX-MS/MS titration workflow with electron capture dissociation (ECD) fragmentation capable of estimating apparent dissociation constants (K(D)(app)) at global, peptide, and single amino acid resolution by fitting uptake-concentration relationships under EX2 exchange and Langmuir binding assumptions. The ability to determine affinity constants in a spatially resolved manner combined with the automation available in HDX-MS sample handling and data analysis enables quantitative mapping of ligand-protein interactions and provides a scalable approach for structure-activity relationship studies in drug discovery. Residue-Level Determination of Small-Molecule-Protein Affinities by Hydrogen-Deuterium Exchange Mass Spectrometry.,Lin D, Magalhaes LG, McMillan J, Eadsforth TC, Stewart G, Cartmill KR, Postis VLG, Masson GR J Am Soc Mass Spectrom. 2026 Mar 31. doi: 10.1021/jasms.6c00020. PMID:41915381[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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