The template molecule is represented as a three-dimensional molecular graph 𝐺 52 = {𝑉 52 , 𝐸 52 , 𝑅 52 } . Several ways of fuzzy operation were applied on 𝐺 52 to increase its structural obscurity aiming to output solutions having low 2D similarity. As shown in Figure , in total, seven different fuzzy operations were adopted in Diff-Shape to achieve varying effects. These operations include: (1) none fuzzy level, in which the original reference molecular graph is used; (2) fuzzy element level, a whitened molecular graph in which all atoms were changed to carbon element and the original bond type information was retained;