arXiv:2512.20333cs.AIq-bio.QM2025-12被引 1

用大模型预测分子编辑序列,让难合成的分子变易合成。

SynCraft: Guiding Large Language Models to Predict Edit Sequences for Molecular Synthesizability Optimization

  • 通过预测原子级编辑序列优化分子可合成性。
  • 生成分子的可合成率显著提升,结构相似度保持高。
  • 适合药物研发中需要兼顾活性与可合成性的场景。

生成式人工智能已革新化学空间探索,但大量生成分子难以合成仍是关键瓶颈。现有方法如事后筛选或基于投影的方案常牺牲结构新颖性或破坏关键药效团。本文提出SynCraft,一种基于推理的框架,将可合成性优化重构为精准的结构编辑问题。利用大语言模型的涌现推理能力,SynCraft在“合成悬崖”区域实现微小结构修改即大幅提升合成可行性。通过预测可执行的原子级编辑序列而非直接生成SMILES,避免了语言模型的语法脆弱性,同时发挥其化学直觉优势。大量基准测试显示,SynCraft在生成高结构保真度且可合成的类似物方面优于现有最优基线。此外,通过交互感知提示,成功复现专家药物化学家对PLK1抑制剂的编辑策略,并挽救了此前文献中高分但被放弃的RIPK1候选分子。

原文摘要 · Abstract (English)

Generative artificial intelligence has revolutionized the exploration of chemical space, yet a critical bottleneck remains that a substantial fraction of generated molecules is synthetically inaccessible. Current solutions, such as post-hoc filtering or projection-based methods, often compromise structural novelty or disrupt key pharmacophores by forcing molecules into pre-defined synthetic templates. Herein, we introduce SynCraft, a reasoning-based framework that reframes synthesizability optimization not as a sequence translation task, but as a precise structural editing problem. Leveraging the emergent reasoning capabilities of Large Language Models, SynCraft navigates the "synthesis cliff" where minimal structural modifications yield significant gains in synthetic feasibility. By predicting executable sequences of atom-level edits rather than generating SMILES strings directly, SynCraft circumvents the syntactic fragility of LLMs while harnessing their chemical intuition. Extensive benchmarks demonstrate that SynCraft outperforms state-of-the-art baselines in generating synthesizable analogs with high structural fidelity. Furthermore, through interaction-aware prompting, SynCraft successfully replicates expert medicinal chemistry intuition in editing PLK1 inhibitors and rescuing high-scoring but previously discarded RIPK1 candidates in previous molecular generation literatures.

分子生成大模型药物设计可合成性

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