Targeting Ligand Shape While Preserving a Warhead through Guided Diffusion and Adaptive Staged Growth
Castanon, I.
Show abstract
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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.