Note that the unfragmented ligands cannot be used in the recombination algorithm (because no attachment point resulting from the fragmentation could be assigned). This could be seen as a restriction in available chemical space of the current approach, since each fragmentlike molecule can be seen as a potential starting point for fragment growing. Nevertheless, roughly 28% of the unfragmented ligands were found to be substructures of other original ligands. More than half of these unfragmented ligands are fragment-like (i.e. fulfill the rule of three 31 ). Thus, they are implicitly used in the introduced recombination approach. The remaining 72% unfragmented ligands are however not considered, a limitation which could be addressed by manually adding attachment points on relevant positions.