Targeting Ligand Shape While Preserving a Warhead through Guided Diffusion and Adaptive Staged Growth
Fragment-based growth models exploit pre-existing structures but can become constrained by early autoregressive decisions and generally lack knowledge of the final target shape. Here, we tested whether geometric guidance applied to a pretrained DiffSBDD model could steer generation toward the shape of a ligand B while preserving a warhead from ligand A. One-shot guidance increased target-volume coverage but predominantly produced disconnected structures. Reformulating the task as smaller scaffold expansions substantially improved the recovery of connected anchor components. Target-directed selection and adaptive growth increments enabled progressive movement toward B, while beam search improved endpoint recovery. Soft-scaffold inpainting provided graded control over the mobility of the inherited scaffold while preserving the fixed warhead. Together, these results show that inference-time shape guidance can be converted from disconnected volume coverage into controlled staged molecular growth, although performance remains dependent on the geometric compatibility of the ligand pair.