To gain a closer insight into the pairwise relationships among the selected drug pairs, we represented each pair in the form of a reaction SMILES considering the conversion of one drug into the other. Form the reaction SMILES, we then computed the differential reaction fingerprint (DRFP), which encodes the circular substructures that occur only in either the reactant or the product. To represent the DRFP chemical space illustrating the similarities between different drug pairs, we then computed a tree-map (TMAP) providing an overview of drug pairs in each of the three datasets, using various color codes to visualize pair properties (Figure ). The TMAP of DRFP similarities organized pairs by structural types, often series of close analogs of a reference drug. Furthermore, in the FDA-approved drug set, different compound families such as amino acids, steroids, β-lactams, catecholamines, benzodiazepines or prostaglandins appeared in different regions of the map. This was visible upon close inspection of the interactive TMAPs and is illustrated here for the FDA drug set with the color FCsp 3 (Figure ).