Virtual screening (VS) approaches utilizing molecular docking are a common choice in the early stages of structure-based drug discovery projects. Typically, their objective is to find initial small molecule hits predicted to bind to a previously unexplored target, or to discover novel scaffolds in an unbiased way when confirmed binders of the studied target are already known. Especially in the initial screening steps, VS often utilizes large and diverse screening libraries to pool the most promising candidates from a large chemical space. Chemical libraries of off-the-shelf or readily synthesizable (make-on-demand) compounds are popular to ensure that the docking predictions can be validated in biochemical assays in a timely manner without the need to factor in potentially time-consuming organic synthesis. In recent years, such libraries have continuously grown and today often cover a vast chemical space with compound numbers on the billion scale. For example, at the beginning of this project, the Enamine REAL library of lead-like compounds had a size of 1.56 billion (March 2021), whereas the current version has 3.93 billion compounds (August 2023). What is a huge leap forward in terms of access to diverse chemical space and straightforward validation of docking-based hypotheses, at the same time becomes a challenge for docking-based VS: Since conventional brute-force docking visits every compound in a chemical library, screening billions of compounds is often no longer feasible, both in terms of the required time and the computational power.