The evolving role of hydrogen/deuterium exchange mass spectrometry in early-stage drug discovery

Protein function relies on protein dynamics and therefore dynamical information can be crucial for drug discovery of challenging protein targets. Assessing protein dynamics experimentally has traditionally been nontrivial. However, amide hydrogen/deuterium exchange mass spectrometry (HDX-MS) is now an established technique that can expose details about changes in protein dynamics, binding sites and allostery at the peptide level. HDX-MS is a versatile and powerful biophysical tool to gain insights into the workings of numerous protein systems and complexes. Advances in instrumentation, automation, data analysis, and interpretation over the past two decades have led to increased uptake and democratization of HDX-MS in both academic and industry settings. Here, we outline the current uses of HDX-MS in early-stage drug discovery and illustrate the interplay with computational chemistry to maximize the value of data obtained from HDX-MS experiments. Finally, we consider approaches which may aid structural interpretation of HDX-MS data in the coming years.