让分子优化既好用又可合成,还能保持多样性。
PGFS++: Molecular Property Improvement under Synthesis and Diversity Constraints

- 用可学习的反应模板和试剂嵌入,直接优化合成路径。
- 在保持高多样性前提下,显著提升分子药效等属性。
- 适合药物研发中需要定制化、可合成分子的场景。
早期药物发现中,提升分子性质(如类药性或结合亲和力)是常见任务。然而,在无约束化学空间中优化的分子若无法合成,则实用性有限。现有合成感知强化学习方法PGFS通过预测反应物嵌入来选择试剂,方式间接,限制了学习效果。为此,我们提出PGFS+,将反应模板和第二反应物表示为可学习的嵌入查找表,并结合更有效的评分函数与强化学习算法,显著提升了目标性质。但该方法暴露了奖励劫持问题:强大的反应物搜索可能将多样输入映射到同一高奖励‘磁性分子’,导致输出多样性坍塌。因此,我们进一步提出PGFS++,一种面向输入特定分子改进的合成感知强化学习框架。给定输入分子,PGFS++将其作为正向合成轨迹起点,使用学习到的反应模板与现成建筑块生成目标性质更优、具有明确合成路径且结构相似于输入的新分子。实验表明,PGFS++在提升目标性质的同时,有效保持了高输出多样性。
原文摘要 · Abstract (English)
Improving molecular properties, such as drug-likeness or binding affinity, is a recurring task in early-stage drug discovery. However, molecules optimized in an unconstrained chemical space have limited practical value if they cannot be synthesized. Policy Gradient for Forward Synthesis (PGFS) is a synthesis-aware reinforcement learning method for molecular improvement, but its use of reactant embedding prediction makes reactant selection indirect, which, as we show, limits learning effectiveness. We first develop PGFS+, in which reaction templates and second reactants are represented by trainable embedding lookup tables. Combined with a more effective scoring function and RL algorithm, PGFS+ significantly improves the desired property. However, it exposes a reward-hacking failure mode: a powerful reactant search can map diverse input molecules to the same high-reward magnet molecule, improving the reward while collapsing the output diversity. We therefore introduce PGFS++, a synthesis-aware reinforcement learning framework for input-specific molecular improvement. Given an input molecule, PGFS++ treats it as the start of a forward-synthesis trajectory, applies learned reaction templates with compatible in-stock building blocks, and produces a molecule with improved target properties, an explicit synthesis route, and structural similarity to the input. Experiments on molecular improvement tasks show that PGFS++ improves target properties while preserving high output diversity.
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