Only ligands with reliable potency values were selected to retain high-quality reference experimental data. As such, we filtered out ligands without an exact potency value (e.g., having '<' , '>' , or '~' symbols) in the PDBbind 34 , Binding DB, and the Binding MOAD. To broaden the access to as many compounds as possible, the potency parameter selected was the IC50 instead of other values present in fewer compounds (i.e., Kd or ki). We are aware of the lack of consistency in the IC50 values between different assays and experimental conditions, and the effect it has on the validation of our predictions. The datasets were constructed with matched pairs with similar potency (non-cliff) and high potency differences (cliffs). This was done to enable an analysis of the method's performance in a realistic situation. Activity cliffs are defined by a high disparity in potency and a high structural similarity. Most authors agree on using a 100-fold difference (i.e., -2.73 kcal•mol -1 at 300 K) as a potency threshold to classify transformations as activity cliffs. However, there is less consensus for the thresholds on structural similarity. Fingerprint-based numerical similarity allows the study of a wider variety of changes. Thus, we used MACCS key fingerprints coupled with the Tanimoto coefficient to maximize the available cliffs.