通过多方法交叉验证,揭示药物靶点相互作用模型的注意力机制。
Where Black-box Drug-Target Interaction Prediction Models Look: Cross-Method Explainability

- 融合梯度与遮蔽法,跨模型对比解释结果
- 发现序列、图结构和化学片段的显著敏感性
- 帮助识别模型偏差,指导后续实验验证
药物-靶点相互作用(DTI)与亲和力(DTA)预测模型性能不断提升,但其对序列、指纹和图特征的内部使用仍不透明。本研究对BridgeDPI架构在Gao、Human和C.elegans三个数据集上的表现进行了可解释性审计。结合集成梯度、梯度显著性、层间相关传播、SmoothGrad及SmoothGrad-IG等梯度方法,辅以特征级遮蔽消融,并通过严格的方法间交集共识降低单一解释器偏差。分析涵盖原始输入、桥接相似性骨架以及图卷积过程中的敏感性,包括边级敏感性和目标边移除效果。结果表明,可解释性作为模型批判工具最有效:揭示了模态主导性、填充与特殊标记的伪影、层间协同或抑制效应的依赖数据特性,以及方法一致的化学一致片段与组成模式。这些分析虽不能替代结构或实验真值,但可为计算药物发现流程提供可验证假设。更广泛而言,将现代XAI应用于当前的DTI/DTA模型,仍是探索训练权重与数据隐含结构的第一步,但这一初步审视已有助于研究人员将预测与药物及靶点表示关联,并优先选择外部验证方向。
原文摘要 · Abstract (English)
Drug-target interaction (DTI) and affinity (DTA) predictors increasingly achieve strong benchmark scores, yet their internal use of sequence, fingerprint, and graph features often remains opaque. We present an interpretability audit of BridgeDPI architecture on three different datasets including Gao, Human, and C.elegans. This study combines gradient-based attributions -- integrated gradients, saliency, layer-wise relevance propagation, SmoothGrad, and SmoothGrad-IG -- with feature-wise occlusion ablation and strict intersection consensus across methods to reduce single-explainer bias. We summarize sensitivity and signed effects at raw inputs, at the bridge similarity scaffold, and through the graph convolution, including edge-level sensitivities and targeted edge removals. The results show that explainability is most informative when treated as model criticism: it reveals modality dominance, padding and special-token artifacts, dataset-dependent cooperative versus suppressive effects across layers, and chemistry-consistent fragment and composition motifs where methods agree. These analyses do not substitute for structural or experimental ground truth, yet they can provide testable hypotheses for downstream validation in computational drug discovery pipelines. More broadly, applying modern XAI to contemporary DTI/DTA models is still an early pass over the rich structure implicit in trained weights and data -- yet even this first layer of scrutiny already helps researchers relate predictions to drug- and target-side representations and to prioritize external validation.
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