Deciphering Scientific Reasoning Steps from Outcome Data for Molecule Optimization
Organizations: Zhongguancun Academy · School of Computer Science and Technology, University of Science and Technology of China · Global Health Drug Discovery Institute
Abstract
Emerging reasoning models hold promise for automating scientific discovery. However, their training is hindered by a critical supervision gap: experimental outcomes are abundant, whereas intermediate reasoning steps are rarely documented at scale. To bridge this gap, we propose DESRO, a framework for deciphering scientific reasoning from outcomes. By analyzing shared patterns and key differences within grouped data, a large language model (LLM) can recover the underlying logic. We instantiate this framework in molecule optimization, a pivotal stage in drug discovery that traditionally relies on the iterative reasoning of medicinal chemists. Across 2.3 million molecular property records, our framework infers optimization rationales by grouping molecules with shared fragments, then using an LLM to analyze how structural variations correlate with property differences. Based on the derived data, we train a model that conducts molecule optimization through an interpretable reasoning process. DESRO achieves the highest success rates on 15 out of 18 tasks, spanning both single- and multi-property optimization of bioactivity and ADMET properties. The reasoning process enables robust generalization to out-of-distribution scenarios, including novel property combinations, unseen biological targets, and unseen properties defined solely by natural language descriptions. In retrospective case studies under strict temporal splits, the model autonomously reconstructs expert-level lead optimization trajectories. Additionally, our framework extends beyond molecule optimization to reaction ligand selection. Our results establish deciphering reasoning steps from outcome data as a viable paradigm for enabling scientific reasoning, providing a scalable approach to accelerate scientific discovery.
Figures & tables
| Category | Property | Predictor / Scorer | Reliability |
| In-Domain Properties | |||
| Bioactivity | DRD2 | tdc.Oracle [ 93 ] | AUROC= |
| JNK3 | AUC = 0.983 | ||
| GSK3 | AUC = 0.984 | ||
| ADMET | BBBP | ADMET-AI Platform [ 95 ] | AUROC = |
| HIA | AUROC= | ||
Appendix figures & tables9 assets
Supplementary material from the paper’s appendix.
Appendix
| Property | Data source | |
|---|---|---|
| Bioactivity | PubChem | |
| Bioactivity (DRD2) | GeLLMO | 0.2 |
| Bioactivity (JNK3) | Synthetic | 0.1 |
| Bioactivity (GSK3 ) | Synthetic | 0.1 |
| BBBP | Prompt-MolOpt | and |
| BBBP | GeLLMO | 0.2 |
| Template |
|---|
| Bioactivity |
| Design a molecule by optimizing {mol1} to enhance its binding affinity with {target_name}. |
| Given {target_name}, suggest modifications to {mol1} to create a new molecule. |
| How can {mol1} be modified to better interact with {target_name}? |
| To enhance the binding of {mol1} with {target_name}, how can it be optimized? |
| What changes can be made to {mol1} to improve its affinity for {target_name}? |
| Template |
|---|
| BBBP |
| Enhance the BBB penetration capability of {mol1}. |
| Boost the ability of {mol1} to cross the BBB. |
| Enhance the ability of {mol1} to cross the blood-brain barrier. |
| Water solubility |
| Boost the solubility of {mol1} in water. |
Scientific Reasoning in Language Models
Scientific reasoning in language models studies how AI systems use evidence, domain knowledge, and tools to solve problems and support discovery.
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