We also investigated the effect of different docking constraints, such as enforcing a docked pose to interact with specific sub-pockets based on pharmacophoric features. The default constraints used for all seven experiments required either a hydrogen bond donor or acceptor interaction with Asn253 6.55 , and the occupation by a lipophilic moiety of either of the sub-pockets II and III (see Figure ) . These constraints were made stricter on a subset of three crystal structures (4EIY, 5OLH and 6GT3) selected to balance rediscovery of A 2A chemotypes and novelty. Figure shows that stricter docking constraints lead to a greater rediscovery of unique chemotypes. However, it is not predictable whether stricter constraints result in more de novo molecules with known A 2A chemotypes. Enforcing occupation of both lipophilic sub-pockets decreases the number of total molecules with A 2A chemotypes, while requiring both a hydrogen bond donor and acceptor interaction with Asn253 6.55 increases this number.