Emerging trends suggest that larger libraries result in better fitting and better scoring molecules. Consequently, many efforts focus on docking increasingly extensive billion-scale libraries. However, the continuous growth of these virtual libraries poses significant computational challenges, and docking all 4.8 billion enumerated Enamine REAL molecules at a rate of 1s per molecule would take approximately 150 CPU years. Hence, screening enumerated libraries on the scale of tens of billions requires new methods.