Drug discovery relies on the identification of small molecules capable of interacting with protein targets (“hits”). However, many drug-discovery workflows don’t evaluate the impact of hits upon protein form and function until later development phases. Early access to conformational information has the potential to focus hits toward mechanistically important structural states. Moreover, many targets of biological importance exist in more than one conformational state, with important biology associated with transitions between them.

Here, researchers present a discovery pipeline that integrates time-resolved, high-throughput, small-angle x-ray scattering (TR-HT-SAXS). They applied this new workflow to an important mitochondrial protein called apoptosis-inducing factor (AIF). By monitoring AIF states over time, TR-HT-SAXS can identify small molecules that modify the protein’s function, enabling researchers to target the most promising compounds in drug screens.