arXiv:2605.12736cs.LG2026-05

用对比学习提升模板匹配,让化学逆合成预测更准更快。

ConRetroBert: EMA Stabilized Dual Encoders for Template-Based Single-Step Retrosynthesis

论文配图:ConRetroBert: EMA Stabilized Dual Encoders for Template-Based Single-Step Retrosynthesis
图 1 · 摘自论文原文
  • 将模板匹配转为产品与模板的稠密向量检索,提升可解释性。
  • 在USPTO-50k上顶1准确率从50.5%提升至62.4%,达75.4%最优结果。
  • 适合需要可追踪反应路径的药物分子设计与合成规划场景。

基于模板的单步逆合成通过选择并应用显式反应模板预测反应物,使每条预测均可追溯至具体化学转化规则,对合成规划很有价值。但传统方法常被视作不如无模板模型,因模板预测通常被建模为长尾规则库上的全局分类任务。我们认为此局限并非源于模板本身,而是学习范式问题。本文提出ConRetroBert,一种双编码器框架,将模板逆合成重构为密集产品-模板检索,再进行候选集列表排序。第一阶段通过对比预训练建立产品与模板的共享嵌入空间;第二阶段利用挖掘的难负样本集,通过多正例列表损失优化模板排序。为避免模板侧适应干扰难负样本挖掘,模型采用慢速移动平均(EMA)模板编码器构建检索库,同时更新实时模板编码器。在本地USPTO-50k基准上,第二阶段排序使顶1准确率从50.5%提升至61.3%,EMA稳定适配进一步提升至62.4%。从无泄露控制的USPTO-Full检查点微调后,在USPTO-50k上达到75.4%顶1准确率。实验还表明,该方法在罕见模板长尾部分表现优异,且许多正确预测来自非标注正例的替代模板。代码与数据见https://github.com/JahidBasher/ConRetroBert。

原文摘要 · Abstract (English)

Template based single step retrosynthesis predicts reactants by selecting and applying an explicit reaction template, making each prediction traceable to a chemical transformation rule. This is useful for synthesis planning, but template based methods are often viewed as less competitive than template free models because template prediction is commonly formulated as global classification over a long tailed rule library. We argue that this weakness is not inherent to templates, but to the learning formulation. We present ConRetroBert, a dual encoder framework that reframes template based retrosynthesis as dense product template retrieval followed by candidate set listwise ranking. Stage 1 uses contrastive pretraining to learn a shared embedding space between products and reaction templates. Stage 2 refines template ranking over mined hard negative candidate sets with a multi positive listwise objective. To enable template side adaptation without destabilizing hard negative mining, ConRetroBert uses a slow moving exponential moving average template encoder for retrieval bank construction while updating the live template encoder through the ranking loss. On the local USPTO-50k benchmark, Stage 2 candidate set ranking improves top-1 reaction accuracy from 50.5% to 61.3%, while EMA stabilized template adaptation further improves it to 62.4%. Fine tuning from a leakage controlled USPTO-Full checkpoint reaches 75.4% top-1 accuracy on USPTO-50k. We also show that retrieval based template prediction is strong in the long tail of rare templates, and that many correct reactant predictions arise from alternative explicit templates rather than only the recorded positive label. Code and data are available at https://github.com/JahidBasher/ConRetroBert.

逆合成双编码器对比学习化学AI

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