Several other hyperparameter combinations achieved slightly lower but similar performance with reduced construction time and memory usage (Supplementary Figure ). For instance, the HNSW using Morgan fingerprints with a radius of 2 and length of 256, an M of 16, and an efConstruction of 300 exhibited a high pAUC 10 of 0.69 (a 4.2% decrease), yet is more efficient: only requiring 42 seconds to construct (36% decrease) and approximately 0.21GB of memory (35% decrease). Construction of a 100-million scale HNSW like those used for AmpC and D4 requires approximately 1.8 hours and occupies approximately 28GB of memory when using the highest performing hyperparameters. Opting for the more efficient but slightly less performant hyperparameters mentioned above would reduce the construction time by approximately a quarter and decrease memory requirements to 18GB. Given these insights, we anticipate that future applications of RAD for ultra-large screening will need to balance performance with computational costs, and we suspect that the easiest way to do this will be by carefully considering the hyperparameter choices.