In recent years, AI-assisted drug design methods have been proposed to generate molecules given the pockets' structures of target proteins. Most of them are atomlevel-based methods, which consider atoms as basic components and generate atom positions and types. In this way, however, it is hard to generate realistic fragments with complicated structures. To solve this, we propose D3FG, a functional-groupbased diffusion model for pocket-specific molecule generation and elaboration. D3FG decomposes molecules into two categories of components: functional groups defined as rigid bodies and linkers as mass points. And the two kinds of components can together form complicated fragments that enhance ligand-protein interactions. To be specific, in the diffusion process, D3FG diffuses the data distribution of the positions, orientations, and types of the components into a prior distribution; In the generative process, the noise is gradually removed from the three variables by denoisers parameterized with designed equivariant graph neural networks. In the experiments, our method can generate molecules with more realistic 3D structures, competitive affinities toward the protein targets, and better drug properties. Besides, D3FG as a solution to a new task of molecule elaboration, could generate molecules with high affinities based on existing ligands and the hotspots of target proteins.

A.1 Molecule Design We present more examples of generated molecules by our method and the CNN baseline liGAN. We select 6 molecules with highest binding affinity for each method and each binding site. The 3 additional binding sites are selected randomly from the testing set. By comparing the samples from two methods, we can find that the 3D molecules generated by our method are generally more realistic, while molecules generated by the baseline have more erroneous structures, such as bonds that are too short and angles that are too sharp. Besides, molecules generated by our method are more diverse, while the 3D atom configurations generated by the baseline are often similar.

This work explores the challenging problem of molecule design by framing it as a conditional generative modeling task, where target biological properties or desired chemical constraints serve as conditioning variables.