donors and acceptors of ≤3, and a cLogP of ≤3. Fragment-based approaches have recently emanated into approved drugs such as vemurafenib and venetoclax. As part of the fragment-based drug design process, the molecular recognition event is carefully (usually by human experience) inspected to determine the crucial proteinligand interactions. As part of this inspection, possible protonation changes upcon complexation can be revealed. For more drugs and advanced drug candidates, such a protonation event is known for several protein families and different ligand chemotypes. These effects are usually not considered even though they apply equally well along the fragment-based drug design process which might lead e.g. to an incorrect set-up of a pharmacophore for a virtual screening campaign resulting in no hits or mis-leading docking hits which assume a false protonation pattern.