用化学性质知识提升逆合成预测准确率,无需重训练模型。
RetroMPA: A Molecular Property-Aware Auxiliary Framework for Enhancing Retrosynthesis Prediction

- 基于分子属性的后处理框架,不改变原模型结构
- 在USPTO-50K上平均提升5.50%准确率
- 可适配各类模型,实验验证了实际合成可行性
逆合成是药物发现与有机合成的核心。尽管数据驱动的深度学习模型进展显著,但它们主要依赖大规模数据自主学习反应模式,缺乏对已有化学知识的显式整合。为此,我们提出RetroMPA,一个分子属性感知的后处理增强模块,将化学知识注入逆合成流程。该模块非独立生成SMILES序列,而是一个通用、模型无关的化学过滤器,可无缝集成于多种数据驱动的逆合成方法中,提升输出质量且无需修改模型架构或重新训练。通过属性感知的潜在嵌入空间,RetroMPA在8个代表性逆合成模型上,于USPTO-50K数据集上平均提升顶1准确率5.50%。此外,在大规模USPTO-Full数据集上,模板匹配与无模板架构均实现约2.03%的平均提升。湿实验验证了其实际应用潜力:成功验证了经典反应(如Suzuki-Miyaura偶联、Bucherer反应、Friedel-Crafts酰化)中此前未报道的底物组合,表明RetroMPA不仅超越数据拟合,还能激发新合成路径。代码已开源。
原文摘要 · Abstract (English)
Retrosynthesis is a cornerstone of drug discovery and organic synthesis. While data-driven deep learning models have shown remarkable progress, they autonomously learn reaction patterns from extensive datasets with limited integration of established chemical knowledge as priors. To address this limitation, we introduce RetroMPA, a molecular property-aware, post-hoc enhancement module that injects chemical knowledge into the retrosynthesis pipeline. Rather than functioning as an independent SMILES sequence generator, RetroMPA is a broadly applicable, model-agnostic chemical filter designed to recalibrate and optimize the predictive pathways of existing algorithms. This plug-and-play framework integrates seamlessly with a range of data-driven retrosynthesis methods, enhancing outputs without modifying model architecture or requiring resource-intensive retraining. By leveraging a property-aware latent embedding space, RetroMPA consistently improves top-1 accuracy across eight representative retrosynthesis models by an average of 5.50% on USPTO-50K. Furthermore, we validate its scalability on the large-scale USPTO-Full dataset, achieving an average improvement of about 2.03% across both template-based and template-free architectures. Wet-lab experiments provide preliminary support for the practical utility of the framework. These syntheses confirmed viable, previously unreported substrate combinations for classic reaction paradigms---specifically, Suzuki-Miyaura coupling, Bucherer reaction, and Friedel-Crafts acylation---suggesting that RetroMPA can operate beyond mere data fitting. The code is open-sourced at https://github.com/MengzhouLu/RetroMPA.
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