Rethinking Molecular OOD Generalization via Target-Aware Source Selection
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arXiv
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| Autori principali: | , , , , , , |
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| Natura: | Preprint |
| Pubblicazione: |
2026
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| _version_ | 1866909041023778816 |
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| author | Lin, Zhuohao Li, Kun Chen, Jiameng Yu, Jiajun Cao, Duanhua Zheng, Yizhen Hu, Wenbin |
| author_facet | Lin, Zhuohao Li, Kun Chen, Jiameng Yu, Jiajun Cao, Duanhua Zheng, Yizhen Hu, Wenbin |
| contents | Robust prediction of molecular properties under extreme out-of-distribution (OOD) scenarios is a pivotal bottleneck in AI-driven drug discovery. Current scaffold-splitting protocols fail to obstruct microscopic semantic overlap, predisposing models to shortcut learning and overestimating their true extrapolation capability; meanwhile, conventional domain adaptation paradigms suffer under extreme structural shifts, as blindly aligning heterogeneous source libraries injects topological noise and triggers negative transfer. To address these two challenges, scaffold-cluster out-of-distribution performance evaluation benchmark (SCOPE-BENCH), a benchmark built on cluster-level partitioning in an explicit physicochemical descriptor space, is proposed alongside policy optimization for multi-source adaptation (POMA), a framework that formulates knowledge transfer as a retrieve-compose-adapt pipeline: labeled source scaffolds structurally close to the unlabeled target are first identified as proxy targets; a reinforcement learning policy then adaptively selects the optimal source subset from an exponentially large candidate pool; and dual-scale domain adaptation is finally performed at macroscopic topological and microscopic pharmacophore scales. Evaluations show that prediction errors of state-of-the-art 3D molecular models surge by up to 8.0x on SCOPE-BENCH with a mean of 5.9x, while POMA achieves up to an 11.2% reduction in mean absolute error with an average relative improvement of 6.2% across diverse backbone architectures. Code is available at https://anonymous.4open.science/r/Molecular-OOD-Code-73F6. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2605_13932 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Rethinking Molecular OOD Generalization via Target-Aware Source Selection Lin, Zhuohao Li, Kun Chen, Jiameng Yu, Jiajun Cao, Duanhua Zheng, Yizhen Hu, Wenbin Machine Learning Robust prediction of molecular properties under extreme out-of-distribution (OOD) scenarios is a pivotal bottleneck in AI-driven drug discovery. Current scaffold-splitting protocols fail to obstruct microscopic semantic overlap, predisposing models to shortcut learning and overestimating their true extrapolation capability; meanwhile, conventional domain adaptation paradigms suffer under extreme structural shifts, as blindly aligning heterogeneous source libraries injects topological noise and triggers negative transfer. To address these two challenges, scaffold-cluster out-of-distribution performance evaluation benchmark (SCOPE-BENCH), a benchmark built on cluster-level partitioning in an explicit physicochemical descriptor space, is proposed alongside policy optimization for multi-source adaptation (POMA), a framework that formulates knowledge transfer as a retrieve-compose-adapt pipeline: labeled source scaffolds structurally close to the unlabeled target are first identified as proxy targets; a reinforcement learning policy then adaptively selects the optimal source subset from an exponentially large candidate pool; and dual-scale domain adaptation is finally performed at macroscopic topological and microscopic pharmacophore scales. Evaluations show that prediction errors of state-of-the-art 3D molecular models surge by up to 8.0x on SCOPE-BENCH with a mean of 5.9x, while POMA achieves up to an 11.2% reduction in mean absolute error with an average relative improvement of 6.2% across diverse backbone architectures. Code is available at https://anonymous.4open.science/r/Molecular-OOD-Code-73F6. |
| title | Rethinking Molecular OOD Generalization via Target-Aware Source Selection |
| topic | Machine Learning |
| url | https://arxiv.org/abs/2605.13932 |