To determine the potential cleaving positions, the co-crystallized ligand of the structure in hand is submitted to an initial fragmentation step, applying the RDKit implementation of the BRICS algorithm. Next, each of the resulting fragments needs to be assigned to a subpocket. Therefore, the geometric center of all atoms (including hydrogens) in the fragment, and its distance to all subpocket centers, is calculated. Then, the fragment is assigned to the subpocket with the closest subpocket center. However, if the closest subpocket to a fragment is more than 8 Å away, this fragment is considered as lying outside of the binding site and assigned to the outlier pool X. Note that the information on the BRICS environment type of each fragment is kept for later recombination.