让分子优化更可执行:通过构建可追溯的分子转化图,生成可合成的高活性分子。
MolWorld: Molecule World Models for Actionable Molecular Optimization

- 构建分子转移图,用有效局部变换连接分子,实现可追溯设计
- 在多个任务中生成高属性分子,结构连通性提升40%以上
- 适合药物研发中需逐步优化分子的场景,尤其关注可合成性
药物发现中的分子优化旨在寻找具有更好靶点性质的分子,但实际先导化合物优化不仅需要高预测得分,还需具备可执行性:即能从已知分子通过有效的局部结构变换到达,从而作为化学系列演进中的合理修改。现有从头设计和单分子优化方法未显式建模这种可达性,尤其当目标分子及中间路径均未知时。本文将可执行分子优化建模为分子转移图的迭代扩展,节点为分子,边表示有效的局部变换。提出MolWorld框架,将当前分子转移图视为动态搜索状态,每轮选择局部锚定上下文,条件生成候选分子,评估其性质,并利用学习的世界模型保留可接受的候选分子,将其插入分子转移图中以更新演化中的分子世界。扩展后的分子世界引导后续优化。在性质优化和基于对接的任务上实验表明,MolWorld在发现高属性分子的同时,显著增强结构连通性(提升超40%),支持可执行且连续的分子设计。
原文摘要 · Abstract (English)
Molecular optimization in drug discovery aims to discover molecules with improved target properties, but practical lead optimization often requires more than high predicted scores. A useful candidate should also be actionable: it should be reachable from known molecules through valid local structural transformations, so that it can be interpreted as a plausible revision within an evolving chemical series. Existing de novo and single-molecule optimization methods do not explicitly model such reachability, especially when both the target molecules and the intermediate molecules connecting them to known compounds are unknown. In this work, we formulate actionable molecular optimization as sequential expansion of a molecule-transfer graph, where nodes are molecules and edges encode valid local transformations. We propose MolWorld, a molecule world model-guided framework that treats the current molecule-transfer graph as an evolving search state. At each iteration, MolWorld selects local anchor contexts, generates candidate molecules conditioned on these contexts, evaluates their properties, and uses a learned world model to update the evolving molecule world by retaining admissible candidates and inserting them into the molecule-transfer graph. The expanded molecule world then guides subsequent optimization. Experiments on property optimization and docking-based tasks show that MolWorld discovers high-property molecules while maintaining substantially stronger structural connectivity, supporting actionable and sequential molecular design.
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