Diversity of hits is important because it provides more potential starting points for hitto-lead optimization. Our random forest was trained only to predict inhibitors and was not concerned with chemical diversity. For the AMS library, we did not filter the selected compounds based on diversity. Rather, we ranked them by predicted activity score and assessed chemical diversity post hoc. When moving to larger synthesize-on-demand libraries like Enamine REAL, diversity requires more formal attention. There are many highly similar or redundant compounds, so prioritizing based on predicted activity alone can concentrate the selected compounds in an undesirably small number of large chemical clusters. When selecting Enamine REAL compounds, we used heuristics such as cluster membership and