The top 10-50 molecules from the 23 generations were re-evaluated with PBE singlepoint calculations, which led to a pool of 299 molecules with PBE refined energies. The energy distribution of these 299 molecules can be seen in Figure . Then, ligands with more than four rotatable bonds were removed, since it is difficult to perform a thorough conformational search on very flexible ligands. Furthermore, we discard molecules with reaction energies for their specific scoring function with ∆E > 20 kcal/mol. This relatively high cutoff is used to minimize the chance of discarding molecules that might have an improved energy score at a higher level of theory. This left us with 141 possible ligand candidates. Next we perform a more thorough conformational search on the 141 ligands, by recalculating the scoring function with 100 conformers for each intermediate and optimize with GFN2-xTB. Here an additional, fifth optimization, is added in addition to the four optimizations performed during GA runs. The final optimization is performed on the full structure with no constraints on the atoms to allow for a full structure relaxation.