Probe Before You Edit: Probing-Guided Molecular Optimization for LLM Agents in Structure-Based Drug Design
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arXiv
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| Autori principali: | , , , |
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| Natura: | Preprint |
| Pubblicazione: |
2026
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| _version_ | 1866917550211727360 |
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| author | Yang, Zaifei Chen, Weiyu Wang, Yaqing Kwok, James |
| author_facet | Yang, Zaifei Chen, Weiyu Wang, Yaqing Kwok, James |
| contents | 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. Inspired by medicinal chemists, who probe the pocket-ligand complex with controlled analog edits before choosing an optimization direction, we propose \textbf{PROBE}, an optimization framework built around edit-response probing. PROBE first decomposes the ligand into editable sites and builds a pocket-specific \textbf{site map} that flags where joint gains are plausible, where the two objectives are likely in tension, and where liability substructures should be changed; it then performs controlled probe edits whose responses are distilled into an \textbf{EditManual}. Guided by the site map and EditManual, PROBE runs an iterative multi-agent loop in which an affinity agent, a druggability agent, and a co-optimization agent jointly produce edits. On the CrossDocked2020 benchmark, PROBE achieves state-of-the-art performance and substantially mitigates the failure modes exposed by our diagnostics metrics. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2606_00555 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Probe Before You Edit: Probing-Guided Molecular Optimization for LLM Agents in Structure-Based Drug Design Yang, Zaifei Chen, Weiyu Wang, Yaqing Kwok, James Artificial Intelligence Biomolecules 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. Inspired by medicinal chemists, who probe the pocket-ligand complex with controlled analog edits before choosing an optimization direction, we propose \textbf{PROBE}, an optimization framework built around edit-response probing. PROBE first decomposes the ligand into editable sites and builds a pocket-specific \textbf{site map} that flags where joint gains are plausible, where the two objectives are likely in tension, and where liability substructures should be changed; it then performs controlled probe edits whose responses are distilled into an \textbf{EditManual}. Guided by the site map and EditManual, PROBE runs an iterative multi-agent loop in which an affinity agent, a druggability agent, and a co-optimization agent jointly produce edits. On the CrossDocked2020 benchmark, PROBE achieves state-of-the-art performance and substantially mitigates the failure modes exposed by our diagnostics metrics. |
| title | Probe Before You Edit: Probing-Guided Molecular Optimization for LLM Agents in Structure-Based Drug Design |
| topic | Artificial Intelligence Biomolecules |
| url | https://arxiv.org/abs/2606.00555 |