Representation-Guided Discrete Molecular Graph Retrosynthesis
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arXiv
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| Main Authors: | , , , , |
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| Format: | Preprint |
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2026
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| _version_ | 1866910250991353856 |
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| author | Huang, Jiahai Qiao, Anjie Wang, Zhen Lian, Defu Lu, Yutong |
| author_facet | Huang, Jiahai Qiao, Anjie Wang, Zhen Lian, Defu Lu, Yutong |
| contents | Stochastic process-based molecular graph generators have become the state of the art for template-free single-step retrosynthesis. However, these models are typically trained only on product-reactant pairs, thereby acquiring chemistry-relevant representations in an indirect and implicit manner. Meanwhile, recent advances in computer vision demonstrate that offering representation guidance to a generator can effectively distill semantics from pretrained encoders into DiTs, substantially improving both convergence and generation quality. Whether similar gains extend to the retrosynthesis task, and what graph-specific design choices can make them work, remains an open question. To address these questions, we conduct a systematic empirical study over a unified design space spanning teacher molecular representations, endpoint and granularity choices, injection depths in the denoiser, correspondence strategies and guidance scheme. Guided by these considerations, we develop Graph-oriented Representation Guidance (GRG), which achieves 58.6 / 77.2 / 83.4 / 87.1 top-1 / 3 / 5 / 10 accuracy on USPTO-50k, while increasing diversity to 15.5, both substantially outperforming the adopted base generator. Notably, GRG consistently improves all top-k metrics in out-of-distribution settings, suggesting that representation guidance facilitates the acquisition of intrinsic chemical semantics. Meanwhile, the introduced representation guidance reduces the number of epochs by 35% and the wall-clock time by 30% to reach comparable performance. In addition, we introduce a simple yet effective representation-similarity-based reranking mechanism, which further improves the top of the ranked list without training an additional verifier. |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2605_24428 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Representation-Guided Discrete Molecular Graph Retrosynthesis Huang, Jiahai Qiao, Anjie Wang, Zhen Lian, Defu Lu, Yutong Machine Learning Stochastic process-based molecular graph generators have become the state of the art for template-free single-step retrosynthesis. However, these models are typically trained only on product-reactant pairs, thereby acquiring chemistry-relevant representations in an indirect and implicit manner. Meanwhile, recent advances in computer vision demonstrate that offering representation guidance to a generator can effectively distill semantics from pretrained encoders into DiTs, substantially improving both convergence and generation quality. Whether similar gains extend to the retrosynthesis task, and what graph-specific design choices can make them work, remains an open question. To address these questions, we conduct a systematic empirical study over a unified design space spanning teacher molecular representations, endpoint and granularity choices, injection depths in the denoiser, correspondence strategies and guidance scheme. Guided by these considerations, we develop Graph-oriented Representation Guidance (GRG), which achieves 58.6 / 77.2 / 83.4 / 87.1 top-1 / 3 / 5 / 10 accuracy on USPTO-50k, while increasing diversity to 15.5, both substantially outperforming the adopted base generator. Notably, GRG consistently improves all top-k metrics in out-of-distribution settings, suggesting that representation guidance facilitates the acquisition of intrinsic chemical semantics. Meanwhile, the introduced representation guidance reduces the number of epochs by 35% and the wall-clock time by 30% to reach comparable performance. In addition, we introduce a simple yet effective representation-similarity-based reranking mechanism, which further improves the top of the ranked list without training an additional verifier. |
| title | Representation-Guided Discrete Molecular Graph Retrosynthesis |
| topic | Machine Learning |
| url | https://arxiv.org/abs/2605.24428 |