Traditional small molecule drug discovery is a time consuming and costly endeavor. High-throughput chemical screening can only assess a tiny fraction of drug-like chemical space. The strong predictive power of modern machine learning methods for virtual chemical screening enables training models on known active and inactive compounds and extrapolating to much larger chemical libraries. However, there has been limited experimental validation of these models' extensibility toward practical applications on large commercially-available or synthesize-on-demand chemical libraries. Through a prospective evaluation with the bacterial protein-protein interaction PriA-SSB, we demonstrate that ligand-based virtual screening can identify many chemically-diverse active compounds in a large commercial library. We use cross validation to compare many supervised learning models and select a random forest classifier as the best model for this target. When predicting the activity of more than 8 million compounds from Aldrich Market Select, the random forest substantially outperforms a naïve baseline based on chemical structure similarity. 48% of the random forest's 701 selected compounds are active. The random forest model easily scales to score one billion compounds from the synthesize-on-demand Enamine REAL database. We tested 68 chemically-diverse top predictions from Enamine REAL and observed 31 hits (46%), including one with an IC50 value of 1.3 µM.