The optimized molecules seem to populate the same region as the split 1 actives that were used for training the OS, as shown by their migration towards the contours in the plot. This suggests that the molecular optimizer finds compounds similar to the actives that were used to obtain the optimization scoring function. This is in fact the case (see Fig. ), as optimized molecules have a more similar neighbour in split 1 than in split 2 on average, as measured by ECFP4 Tanimoto similarity. This shows that at least some of the difference between OS and DCS can be explained by data specific biases.