arXiv:2606.11256physics.chem-phcs.LG2026-06

用大模型指导合成路径进化,高效设计可合成分子。

My Chemical Harness: Evolutionary Molecular Design over Synthetic Pathways with Large Language Model Agents

论文配图:My Chemical Harness: Evolutionary Molecular Design over Synthetic Pathways with Large Language Model Agents
图 1 · 摘自论文原文
  • 以可执行的合成路径为搜索对象,而非孤立分子图
  • 在环氧水解酶任务中达当前最优,三项指标领先
  • 适合药物研发与分子设计领域研究人员

设计具有特定性质的分子最有价值时,候选结构应具备可行的合成路线。我们提出 My Chemical Harness,一种基于合成路径的原生进化框架,用于目标导向的分子设计,其搜索种群由可执行的合成路径构成,而非孤立的分子图。每个路径由可购得的起始物料和反应模板构建,通过确定性化学工具执行,并由任务特定的分子预言机评分。大型语言模型(LLMs)仅作为策略控制器,选择路径长度、反应类型、反应家族、关键片段和探索强度等高层偏好;局部代码负责路径构建、验证、去重、评分、选择与记忆更新。这种分离机制使 LLM 能引导探索,又避免引入幻觉产物或不支持的反应步骤。在可溶性环氧水解酶(sEH)代理任务上,我们的 LLM 代理优于单次运行的 LLM 和确定性控制器,在 sEH 分数、合成可及性分数和 AiZynthFinder 成功率三项指标上达到当前最优。结果表明,受限的 LLM 代理可在无需训练、微调或专用生成模型的前提下,显著推动分子发现。

原文摘要 · Abstract (English)

Designing molecules with target properties is most useful when candidate structures are accompanied by feasible synthetic routes. We introduce My Chemical Harness, a route-native evolutionary framework for goal-directed molecular design in which the search population consists of executable synthetic pathways rather than isolated molecular graphs. Each route is built from purchasable building blocks and reaction templates, executed by deterministic chemistry tools, and scored through task-specific molecular oracles. Large language models (LLMs) are used only as strategy controllers that select high-level preferences over route length, move type, reaction families, motifs, and exploration pressure, while local code performs route construction, validation, deduplication, scoring, selection, and memory updates. This separation lets the LLM guide exploration without allowing it to introduce hallucinated products or unsupported reaction steps. On a soluble epoxide hydrolase proxy task, our LLM agent improves over single pass LLM and deterministic controllers, reaching state-of-the-art performance across the sEH score, synthetic accessibility score, and AiZynthFinder success rate metrics. These results suggest that constrained LLM agents can play a significant role in molecular discovery without requiring training, fine-tuning, or dedicated generative models.

分子设计大模型应用合成路径自动化

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