The shape similarity distributions were analyzed for both the entire generated sets and the best sets, i.e. molecules with the highest shape similarity to each reference. At the same time, we also examined the shape similarity distribution according to 2D similarity cut-off 1.0, 0.7, 0.3. For compounds with 𝑆𝑖𝑚 I < 1.0, the median of 𝑆𝑖𝑚 JK was 0.91 among all generations and 0.96 for the best performers for Diff-Shape-0.