Probe Before You Edit: Probing-Guided Molecular Optimization for LLM Agents in Structure-Based Drug Design

Summary

arXiv:2606.00555v2 Announce Type: replace-cross Abstract: Structure-based drug design increasingly employs LLM agents to iteratively refine ligands against a target pocket, yet a viable ligand must satisfy two often-conflicting objectives -- binding affinity and druggability -- which single optimization steps rarely improve together. To quantify this difficulty, we introduce two diagnostic metrics: the first measures how often a single edit improves both objectives, and the second measures how often a gain on one objective comes with a loss on the other. Applying these diagnostics to current LLM-agent pipelines exposes a consistent failure mode: the agent performs molecular editing without knowing how the pocket-ligand complex responds to local modifications, thus rarely achieving joint improvement.