Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) has been widely adopted as part of the drug development pipeline, frequently used in both the development of biopharmaceuticals and small molecule compound development to assess target engagement spatially. Frequently, HDX-MS analyses are conducted at saturating compound concentrations to produce a compound binding “footprint” where typically the reductions in solvent exchange associated with compound engagement can be interpreted as evidence of a localized hydrogen bond network disruption caused by a binding event. Here we present a workflow of compound titration in both HDX-MS and HDX-MS/MS workflows using ECD to determine compound dissociation constants at a global, peptide and single amino acid resolution. The ability to determine affinity constants in a spatially resolved manner using the automation available to HDX-MS sample production and data analysis is likely to have applications in drug discovery and medicinal chemistry.