Ligand-interacting residues were selected from X-ray kinase structures based on the KLIFS IFP, i.e. 12, 57, 26, and 13 structures have cumulatively 21, 31, 27, and 35 interacting residues with Erlotinib, Imatinib, Bosutinib, and Doramapimod, respectively. In the case of Erlotinib and Bosutinib, the performance improves when including only the ligand-interacting residues -LOK, SLK, and the previously KiSSim-undetected GAK are all in the top 20 most kinase similarities compared to EGFR -, while the performance decreases slightly in the case of Imatinib and Doramapimod (see notebook for more details). Thus, depending on the user's research question such as predicting off-target for one or multiple ligands of interest, known interaction profiles can be used to guide the selection of residues for the KiSSim fingerprint.