用极少量参数在测试时快速适配药物筛选模型,提升精度且不重训练。
PETA:Parameter-Efficient Test-Time Adaptation for Virtual Screening

- 测试时仅调整层归一化参数,实现轻量级模型适配。
- 通过分子扩散生成无效候选,构造更难的排序任务以增强监督。
- 适配后性能超越预训练和全量重训模型,仅更新0.03%参数。
从海量化学库中准确排序目标蛋白口袋的活性配体,仍是虚拟筛选的核心挑战。DrugCLIP及其后续扩展通过将蛋白口袋与分子编码至共享嵌入空间,显著加速该过程。然而,进一步提升性能通常需重新训练整个模型,带来巨大计算开销,导致靶点定制效率低下。本文将预训练虚拟筛选模型针对单个口袋的特化问题定义为测试时适应(test-time adaptation)问题,提出PETA——一种参数高效的框架,在测试时直接适配预训练模型。给定目标口袋,PETA通过分子扩散与化学有效性过滤生成口袋特异性负样本,并利用嵌入空间混合策略将其向结构数据库中检索到的参考配体移动,从而构建更具挑战性的排序任务。通过排名目标强化抑制高分无效候选,防止其污染前排筛选结果,提供结构化监督以支持轻量化适配。在多个基准测试中,该轻量、口袋特异的适配方法优于预训练及全量重训基线,仅更新约0.03%的模型参数。
原文摘要 · Abstract (English)
Accurately ranking active ligands for a target protein pocket from massive chemical libraries remains a central challenge in virtual screening. DrugCLIP and its recent extensions substantially accelerate this process by encoding protein pockets and molecules into a shared embedding space. Despite this progress, further performance improvements typically require retraining the entire model, incurring substantial computational overhead and making target-specific customization inefficient. In this work, we formulate the specialization of pretrained virtual screening models to individual pockets as a test-time adaptation problem and propose PETA, a parameter-efficient framework that directly adapts pretrained model at test time. Given a target pocket, PETA constructs pocket-specific negatives through molecular diffusion and chemical validity filtering, and further moves them toward the reference ligand retrieved from structural databases via embedding-space mixup to create more challenging ranking tasks. A ranking objective then places greater emphasis on suppressing high-scoring invalid candidates that could contaminate the top-ranked screening results, providing structured supervision for lightweight adaptation. Experiments across diverse benchmarks demonstrate that this lightweight, pocket-specific adaptation outperforms both pretrained and fully retrained baselines while updating only the LayerNorm parameters, which account for approximately $0.03\%$ of the full model.
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