but containing a novel cyclo-propane core with two benzene substituents, one in the deep orthosteric pocket and one towards helix 6. Upon searching known 5-HT2A ligands, a precedence is found for such a di-aryl substructure linked by an sp 3 hybridised carbon. To further exemplify the potential benefits of more difficult scoring functions such as this, the protein-ligand interaction fingerprints were computed for the predicted poses of the top 10 5-HT2A de novo molecules and top 10 5-HT2A vs D2 using ProLIF . Figure displays the resulting fingerprints in comparison to the reference ligand, highlighting key areas of the binding pocket avoided by de novo molecules optimised for selectivity, for example, S131 2x60 , Y139, I206 4x56 , S207 4x57 , P209 4x60 , I210 4x61 , L362 7x34 , N363 7x35 . Interestingly, the top10 de novo molecules optimised for selectivity mostly interact with D155 3x32 via polar interactions and not cationic interactions, which may reflect an attempt to avoid increasing D2 docking score (targeting cationic interactions to this residue was a key observation in previous work to optimise the D2 docking score ). Overall, this represents a much more challenging objective for de novo design, however, despite poor numerical divergence of docking scores we have shown that this still impacts de novo chemistry obtained and therefore still has utility in practice.