PETA:Parameter-Efficient Test-Time Adaptation for Virtual Screening

arXiv:2608.19906v1 Announce Type: new Abstract: 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.

Abstract: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.

Machine Learning (cs.LG)

arXiv:2608.19906 [cs.LG]

(or arXiv:2608.19906v1 [cs.LG] for this version)

https://doi.org/10.48550/arXiv.2608.19906 Focus to learn more arXiv-issued DOI via DataCite (pending registration)

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PETA:Parameter-Efficient Test-Time Adaptation for Virtual Screening

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