Figure demonstrates that AHC successfully generated molecules with favourable docking scores for the respective A 2A receptor structure while maintaining secondary objectives within desirable ranges, highlighting the powerful multi-objective optimisation ability of RL and AHC within a restricted budget of just 12,800 molecules. To further understand how the optimisation of the structure-based objective influenced de novo chemistry, we compared the generated molecules to known A 2A receptor ligands (sourced from GPCRBench and updated with new data from ChEMBL29 and Reaxys), classified by chemotype. Figure shows that each crystal structures led to rediscovery of approximately 25 unique chemotypes known to be present in A 2A receptor ligands, except for 6ZDR, which led to the rediscovery of approximately 18. This corresponded to a range of 2,000 to 4,000 molecules per experiment with known A 2A chemotypes out of the 12,800 (~15-30%), indicating alignment between the structurebased objective and known A 2A ligands. Interestingly, only one to two known active molecules were rediscovered per experiment meaning that almost all de novo molecules are novel, providing a significant enrichment around known A 2A ligand chemistry. The number and type of chemotypes rediscovered varied depending on the structure used; for example, only the experiment with the 5OLV structure rediscovers the 2c6 chemotype. All chemotypes rediscovered are detailed in Supplementary Figure .