arXiv:2606.12578cs.CL2026-06

提出可复现的机制级药物相互作用预测方法,精准识别作用靶点与方向。

MARD: Mirror-Augmented Reasoning Distillation for Mechanism-Level Drug-Drug Interaction Prediction

论文配图:MARD: Mirror-Augmented Reasoning Distillation for Mechanism-Level Drug-Drug Interaction Prediction
图 1 · 摘自论文原文
  • 通过镜像增强推理蒸馏,结合方向标签约束与程序化负样本训练。
  • 在新药对上准确率领先基线13.9个百分点,成本仅为前沿API的1%。
  • 适合药物研发人员和药理学研究者,助力安全用药分析。

机制级药物相互作用(DDI)预测需明确涉及的酶或药效通路、作用方向及证据,而不仅是判断是否相互作用。本文提出可复现的机制级DDI标注与评估协议,包含7类/147亚型的结构化分类体系、防泄露冷分割方案以及可审计的推理指标,超越传统二元交互分类。提出MARD(镜像增强推理蒸馏)流水线,生成70亿参数模型,融合三项训练创新:单标记KL散度约束方向预测、基于程序化硬负样本的加权强化学习,以及防泄露的机制感知检索通道。过程-奖励步骤标签可自动验证,无需人工或大模型评判。在2026年4月版DrugBank数据集上,MARD-7B是32系统中唯一在新药对上性能不降的模型,较最优基线提升13.9个百分点,优于GPT-4o 6.7个百分点,仅需约1%的前沿API成本。进一步分析显示其具有反记忆特征——罕见药物对准确率反而上升,表明性能源于结构化药理推理而非药物频率记忆。论文发布数据集、DDI-PRM、检索索引与训练代码。

原文摘要 · Abstract (English)

Mechanism-level drug-drug interaction (DDI) prediction requires identifying which enzyme or pharmacodynamic axis is implicated, in which direction, and with which evidence -- not merely whether two drugs interact. We introduce a reproducible mechanism-level DDI labelling and evaluation protocol with a structured 7-family/147-subtype taxonomy, leakage-safe cold-split protocols, and auditable reasoning metrics for evaluating pharmacological prediction beyond flat interaction classification. We propose a pipeline that produces a 7B reasoning MARD (Mirror-Augmented Reasoning Distillation), combining three training innovations: a single-token KL divergence on direction tag that ties the model's prediction, per-loss PRM-weighted DPO with programmatic hard negatives, and a leakage-safe mechanism-aware retrieval channel. Process-reward step labels are automatically verifiable against DrugBank-structured fields, requiring no human or LLM judges. On the April-2026 DrugBank release, our MARD-7B is the only system in a 32-system comparison whose accuracy survives drug-pair novelty, beating the best baseline by +13.9 pp and GPT-4o by +6.7 pp at ~1% of frontier API cost. Further analysis reveals an anti-memorisation signature where accuracy improves on rarely seen drugs, suggesting that gain comes from structured pharmacological reasoning rather than drug-frequency memorisation. We release corpus, DDI-PRM, retrieval index, and training code.

药物相互作用推理蒸馏药理学知识增强

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