arXiv:2605.25681cs.LGcs.AI2026-05

不重训练模型,用冻结的单靶点生成器找回双靶点分子。

Don't Retrain, Just Reuse: Recovering Dual-Target Molecules from Single-Target Diffusion Models

论文配图:Don't Retrain, Just Reuse: Recovering Dual-Target Molecules from Single-Target Diffusion Models
图 1 · 摘自论文原文
  • 通过优化输入噪声而非分子结构,从冻结模型中恢复双靶点分子。
  • 在双靶点亲和力上比最强基线提升21.1个百分点,且保持药物可行性。
  • 适合需要快速生成双靶点候选药的药物研发人员使用。

设计能同时调节两个靶点的分子是多靶点药物的重要策略,但相比单靶点生成更具挑战性——需同时满足两个结合要求,且保持类药性和可合成性。现有方法通常通过重训练生成器或采样时干预扩散过程来实现双靶点能力,前者成本高、难稳定,后者对去噪时间的目标平衡敏感,更新方向易冲突。为此,本文提出一种保留生成器原状的替代方案:能否在不修改参数或去噪动态的前提下,从冻结的单靶点扩散模型输入空间中恢复双靶点分子?我们将其建模为约束多目标优化问题,提出REUSE方法,通过演化模型输入噪声而非分子结构进行搜索。每个输入被多次解码,基于生成分子家族的整体质量评分。候选分子分阶段筛选:低成本评估优先过滤化学不可行分子,完整对接保留给精简后的候选集,最终联合选出兼具多样性与双靶点强亲和力的分子组合。实验表明,REUSE在双靶点亲和力上优于现有基线,双高亲和力指标提升21.1个百分点,同时维持与常用化学可行性标准一致的QED和SA得分。

原文摘要 · Abstract (English)

Designing a single molecule that modulates two targets is a promising strategy for polypharmacology, but it remains substantially harder than standard single-target generation because one candidate must satisfy two binding requirements while preserving drug-likeness and synthesizability. Existing dual-target generative methods typically introduce dual-target capability by either retraining the generator or intervening in the diffusion process during sampling. The former can be costly and difficult to stabilize when dual-target supervision is sparse, while the latter may be sensitive to denoising-time target balancing and competing update directions. These limitations motivate a generator-preserving alternative that keeps the pretrained prior intact: can dual-target candidates instead be recovered from the input space of a frozen single-target diffusion model, without modifying its parameters or denoising dynamics? We formulate this task as a constrained multi-objective optimization problem and propose REUSE, which evolves the input noise of a frozen diffusion generator rather than molecular structures. Each input is decoded multiple times and scored by the collective quality of the generated molecular family. Candidates are then screened progressively: lower-cost evaluations prioritize molecules satisfying chemical-feasibility criteria, full docking is reserved for a reduced frontier, and the survivors are jointly selected as a diverse panel with strong affinity to both targets. Experiments show that REUSE achieves stronger and more balanced dual-target recovery than prior dual-target baselines, improving Dual High Affinity by 21.1 percentage points over the strongest prior baseline while retaining QED and SA profiles consistent with commonly used chemical-feasibility criteria.

分子生成双靶点扩散模型药物发现

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