AI and the World's Hard Problems · Medicine & drug discovery · arXiv · 2026-10-26
Probe Before You Edit: Probing-Guided Molecular Optimization for LLM Agents in Structure-Based Drug Design
Structure-based drug design with LLM agents often struggles to improve binding affinity and druggability together. The authors introduce two diagnostic metrics and find that current agents edit ligands without knowing how the pocket responds, so joint gains are rare. They propose PROBE, which builds a pocket-specific site map, runs controlled probe edits, and uses the results in an iterative multi-agent optimization loop. On the CrossDocked2020 benchmark, PROBE reports state-of-the-art performance and substantially mitigates the failure modes the diagnostics revealed.