DockStream can be specified as a component to REINVENT (see Supporting Information Fig. for more details), conferring the ability to incorporate molecular docking into 𝑆(𝑥). While it is straightforward to impose docking score optimization in REINVENT, defining a useful docking configuration remains challenging. Ideally, the docking score should be biased to either exhibit high correlation with experimental activity or at least be able to distinguish active and decoy ligands. Similar to using DockStream as a stand-alone docking tool, the benchmarking and analysis workflow (Fig. ) can be used to automate search for such a docking configuration. There are two use cases: