Recombination procedure. All possible fragment combinations of the above described reduced set were enumerated, while preserving the original subpocket connections when connecting the fragmented bonds using the subpocket-labeled dummy atoms. Recombination started from AP fragments only, while fragments from other subpockets were consecutively added, thereby excluding any recombined molecules not occupying AP. Fragments were combined by adding a bond between two atoms adjacent to dummy atoms, while removing the dummy atoms. Thereby, two fragments were connected via a new bond between two atoms if the following conditions were fulfilled: (i) The first fragment's dummy atom was associated with the same subpocket as the second fragment and vice versa. (ii) The BRICS environment types of the atoms to be connected were matching according to the BRICS rules, in order to preserve synthetic accessibility. The bond type (single or double bond) between dummy atoms was preserved when connecting the fragments. (iii) While connecting the fragments, it was ensured that the resulting molecule did not contain two fragments from the same subpocket, i.e. to occupy one subpocket multiple times.