where the cyclic moiety would sit deep in the hydrophobic sub-pocket and the amine would form a salt bridge with D114 3x32 . The only difference between the RL strategies appears to be the better docking scores achieved by AHC. However, as σ increases (180-240), de novo molecules are clearly much larger and therefore exploiting the additive nature of the docking scoring function . This corroborates the observation of extrapolation into restricted property space seen in Figure and g, which enables this exploitation. In this scenario added constraints would be necessary in a multi-parameter optimization setting, such as also defining a suitable molecular weight range as this knowledge is no longer imposed by the prior dataset. We believe these results highlight the balance that is required in the tradeoff between regularization and optimization, which is better achieved by AHC than REINVENT.