For ligand atoms, reference atoms for restraints can be chosen either automatically or by the user. The latter can be very useful if a ligand series has a structural element that is known to be stable or to be involved in key interactions in the binding site. We implemented an option for users to define their selections through a substructure search via SMARTS patterns. Automatic selection of ligand atoms on the other hand can be used when no prior information on stable ligand groups is available or if the series does not share a common group. Here, the algorithm selects ligand atoms in a central ring system since a central ring system is likely more stable than other parts of the molecule.