MolEvolve: LLM-Guided Evolutionary Search for Interpretable Molecular Optimization

Molecular optimization, the process of designing molecules with desirable properties, represents a critical challenge in drug discovery. The recent advancements in large language models (LLMs) have opened new opportunities for their integration with traditional molecular optimization algorithms to improve performance. In this work, we propose Molecular Language Model powered Evolutionary Algorithm (Mol-E), an evolutionary algorithm that relies on the generative capabilities of LLMs trained on molecules and molecular properties. Scientific Contribution. Mol-E obtains the highest aggregate Top-10 AUC among the comparable full-23-task results considered here, scoring 17.500 in the task-agnostic regime, in which the oracle is treated strictly as a black box, and 20.551 in the task-informed regime, in which the optimizer receives a fixed semantic description of the objective. Mol-E also improves over the evaluated baselines on multi-property optimization with docking against DRD2, MK2, and AChE.

Designing molecules with target properties is most useful when candidate structures are accompanied by feasible synthetic routes. We introduce My Chemical Harness, a route-native evolutionary framework for goal-directed molecular design in which the search population consists of executable synthetic pathways rather than isolated molecular graphs. Each route is built from purchasable building blocks and reaction templates, executed by deterministic chemistry tools, and scored through task-specific molecular oracles. Large language models (LLMs) are used only as strategy controllers that select high-level preferences over route length, move type, reaction families, motifs, and exploration pressure, while local code performs route construction, validation, deduplication, scoring, selection, and memory updates. This separation lets the LLM guide exploration without allowing it to introduce hallucinated products or unsupported reaction steps. On a soluble epoxide hydrolase proxy task, our LLM agent improves over single pass LLM and deterministic controllers, reaching state-of-the-art performance across the sEH score, synthetic accessibility score, and AiZynthFinder success rate metrics. These results suggest that constrained LLM agents can play a significant role in molecular discovery without requiring training, fine-tuning, or dedicated generative models.

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.