As previously established, the protein structure used influences the resulting de novo chemistry. We also tested further modifications, such as the effect of fine-tuning the CLM on an A 2A receptor ligand dataset prior to applying AHC. While this initially increased the number of unique chemotypes rediscovered, the number decreased over time due to the diversity filter penalising repeated areas of chemical space. By the end of the AHC-based optimisation the non-fine-tuned CLM generated a higher proportion of molecules with known A 2A chemotypes (see Supplementary Figure ), indicating that the effect of fine-tuning the CLM is short-lived as RL updates the model parameters.