arXiv:2608.02688cs.LGcs.AI2026-08

让分子结构在表型数据中保持原貌,提升药物发现精度

Learning Molecular Representations from Cellular Phenotypes with Structure Preservation

论文配图:Learning Molecular Representations from Cellular Phenotypes with Structure Preservation
图 1 · 摘自论文原文
  • 分离分子与细胞表示,通过专用分支保结构
  • 在3万组分子-表型数据上提升270项生物活性预测性能
  • 适合需要保留化学结构信息的药物研发人员

表型药物发现可揭示分子结构与细胞响应间的功能关系。现有多模态表示学习方法常忽略化学空间的内在组织,导致分子表示失真、结构信息丢失。我们提出PhenMol,一种面向表型的结构保持型分子表示学习框架。该方法将分子与细胞表示分解为共享和私有成分,通过专用分子分支实现表型引导对齐,同时保持化学结构的邻域关系。在约3.04×10⁴个分子-细胞形态配对数据上验证,PhenMol在270项生物活性任务中提升分子性质预测效果,改善分子-表型检索与临床试验结果预测能力。基于ECFP4的结构分析显示,相较于现有方法,PhenMol更有效保持分子邻域结构,减少嵌入失真。结果表明,结构感知约束对多模态分子表示学习至关重要,为整合细胞表型与化学知识提供有效路径。

原文摘要 · Abstract (English)

Phenotypic drug discovery enables the discovery of functional relationships between molecular structures and cellular responses. However, existing multimodal representation learning methods often optimize cross-modal alignment without considering the intrinsic organization of chemical space, resulting in distorted molecular representations and loss of structural information. We propose \textbf{PhenMol}, a structure-preserving framework for phenotype-aware molecular representation learning. PhenMol disentangles molecular and cellular representations into shared and private components, enabling phenotype-guided alignment while preserving chemical structures through a dedicated molecular branch. This design integrates cellular phenotype information without disrupting molecular neighborhood organization. Experiments on approximately $3.04 \times 10^{4}$ molecule--cell morphology pairs demonstrate that PhenMol improves molecular property prediction across 270 bioactivity tasks, molecule--phenotype retrieval, and clinical trial outcome prediction. Moreover, ECFP4-based structural analysis shows that PhenMol better preserves molecular neighborhoods and reduces embedding distortion compared with existing multimodal alignment methods. These results highlight the importance of structure-aware constraints in multimodal molecular representation learning and provide an effective approach for integrating cellular phenotypes with chemical knowledge for drug discovery.

分子表示表型分析药物发现结构保持

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