FragFlex: Fragment-Based Flexible Molecular Generation for Exploring Vast Chemical Space
Sihyun Park, David Ryan Koes
Abstract
Drug discovery requires efficient exploration of an astronomically large chemical space. Molecular graph diffusion models offer a promising approach to this task, but many require graph size to be fixed before generation. Although atom-level insertion and deletion can enable flexible-size generation, jointly modeling molecular size, atom types, and bonds while maintaining chemical validity remains challenging. We introduce FragFlex, a flexible-length discrete diffusion model that performs node insertion and deletion at the fragment level. During denoising, FragFlex jointly learns the size, fragment identities, and inter-fragment connectivity of the fragment graph. A neural attachment-site predictor and valence-aware assembler then convert the generated fragment graph into an atom-level molecule. In large-scale experiments generating 10 million molecules, FragFlex achieves near-perfect chemical validity while maintaining high uniqueness, demonstrating a strong balance between the two.