提出可验证的药物协同作用解释框架,精准定位两药共同作用的分子区域。
VINCENT: Validated Interaction Network for Cross-drug Explanation of Therapeutics

- 通过注意力与梯度信号提取原子对证据,分组为化学一致的基团。
- 在71组测试中,交叉药物作用得分区分真阳/真阴达3.36,文献召回率达0.826。
- 闭环扰动验证机制确保解释稳定、可信,适合药物研发人员使用。
药物协同效应预测旨在判断两种药物联用是否比单独使用产生更强效果。单一协同评分不足以支持药物发现:研究者还需明确哪些分子区域共同驱动该预测。本文研究基团对协同解释,即识别来自每种药物的化学连贯区域组合,这些区域共同贡献于预测的协同效应。现有可解释模型暴露原子或子结构级信号,但其解释嵌入预测器架构,缺乏对跨药物区域评分在重复扰动下的验证,也未将证据反馈用于优化解释。可靠基团对解释应具备化学一致性、扰动稳定性及与预测行为一致。本文提出VINCENT(用于药物治疗交叉解释的验证交互网络),一个针对固定交互感知协同预测器的后训练框架。VINCENT从注意力与梯度信号中提取原子对证据,将原子聚类为化学一致的基团,并通过重复局部扰动验证候选基团对。经验证的证据被反馈以优化基团分配,生成满足上述三标准的解释。在25对文献标注子集上,VINCENT平均基团召回率达0.826(95%置信区间:0.78–0.87),优于基线模型的0.49–0.66。在全部71组测试对中,其验证后的交互得分实现3.36的真阳性/真阴性分离度。结果表明,闭环扰动验证比现有方法更准确恢复文献支持的分子区域,且生成的跨药物相互作用评分更贴近预测器行为。
原文摘要 · Abstract (English)
Drug synergy prediction estimates whether two drugs produce a stronger joint effect than expected from their individual activities. For drug combination discovery, a single synergy score is often not enough: researchers also need to know which molecular regions jointly drive the prediction. We study motif-pair synergy explanation, which identifies pairs of chemically coherent regions, one from each drug, that jointly contribute to predicted synergy. Existing interpretable synergy models expose atom- or substructure-level signals, but their explanations are built into the predictor architecture, and none validates cross-drug region scores under repeated perturbations or feeds that evidence back to refine the explanation. A reliable motif-pair explanation should instead be chemically coherent, perturbation-stable, and aligned with predictor behavior. We introduce VINCENT (Validated Interaction Network for Cross-drug Explanation of Therapeutics), a post-training framework for a fixed interaction-aware synergy predictor. VINCENT extracts atom-pair evidence from attention and gradient signals, groups atoms into chemically coherent motifs, and validates candidate motif pairs through repeated local perturbations. The validated evidence is fed back to refine motif assignments, yielding explanations that satisfy these three criteria. On a 25-pair literature-annotated subset, VINCENT achieves a mean motif recall of 0.826 (95% CI: 0.78-0.87), compared with 0.49-0.66 for baselines. Across all 71 test pairs, its validated interaction scores yield a TP/TN separation of 3.36. These results show that closed-loop perturbation validation recovers literature-supported molecular regions more accurately than existing alternatives while producing cross-drug interaction scores that better reflect predictor behavior.
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