Overall, structure-based drug design objectives can be efficiently optimized with a CLM and AHC, resulting in the rediscovery of commercially novel but relevant ligand chemistry, dependent on the choice of structure used. last three objectives are annotated 'soft limit' or 'hard limit'. If the respective property is within the soft limit, it is given a score of 1, if it is beyond the hard limit, it is given a score of 0. Between the soft and hard limit, it is linearly scored between one to zero from the soft to hard limit. In (e) and (f) the soft limit is the same as the hard limit. Despite clear enrichment of known A 2A receptor ligand chemistry, the majority of molecules do not possess known chemotypes. However, chemotypes that have multiple corresponding de novo molecules with high scores could represent promising novel chemotypes compared to known A 2A receptor ligands. To identify promising unknown chemotypes, molecules with a GlideSP score less than -10 were pooled across all experiments and unknown chemotypes extracted. Note that of the 10,363 de novo molecules with a GlideSP score less than -10, only 3,101 possessed unknown chemotypes, indicating that at this threshold, known A 2A chemotypes are much more prevalent. The unknown chemotypes were clustered based on a Bemis-Murcko scaffold Tanimoto similarity (using ECFP4 fingerprints) greater than 0.2 and the maximum common substructure of each cluster was identified resulting in 65 chemotypes derived from a cluster containing at least 3 example molecules (see Supplementary Figure ). Many of these chemotypes still display functional groups important for interacting with Asn253 6.55 (Ballesteros-Weinstein generic residue numbers are shown in superscript), and therefore are of interest to validate as potentially novel ligand series.