Furthermore, we curated a list of 50 chemically relevant molecular substructures (Supp. Table ), to monitor chemical space exploration across active learning cycles. We found that exploration (selection of most uncertain molecules) and random acquisition are the best acquisition methods in terms of (global) early enrichment of new substructures (Fig. ). Similarity-based acquisition, by definition, is the slowest at finding novel chemistry. When looking at hit molecules only, exploitation and mutual information-based acquisition yield the highest number of new (unique) substructures (Supp. Fig. ). Hence, in general, mutual information is the acquisition method that overall discovers more hits and provides a high degree of novel substructure exploration (both overall and in the retrieved hits). When normalizing these statistics by the number of hits found by each method (Fig. ), no single method finds novel substructures faster.