For shape-conditioned generative models, the 3D similarities of generated conformations to the reference molecules are also provided. Among all the methods, the molecules generated by Diff-Shape-0.3 exhibit the highest shape similarity for both docking poses and generated conformations, having median 2D similarities of less than 0.4. Comparing to the Diff-Shape-0.3 model, Diff-Shape-0.4 exhibits better diversity with the median 𝑆𝑖𝑚 ,K less than 0.2, and slightly lower shape similarity. This indicates that, guided by the reference molecules, Diff-Shape has the capability in creating novel scaffolds with high shape similarity. Due to the close 3D shape match with the reference molecules, their docking modes are generally consistent with those of references, resulting in more favourable docking scores. The binding poses of the best generation are as shown in Figure , it can be seen that Diff-Shape generations adopt consistent binding mode to the references in all four cases.