Test-Time Adaptation without Source Data for Out-of-Domain Bioactivity Prediction

Yiming Yang, Zhiyuan Zhou, Yueming Yin, Hoi-Yeung Li, Adams Wai-Kin Kong

Keywords: out-of-domain bioactivity prediction, source data-absent, test-time adaptation

TL;DR: We explore a realistic bioactivity prediction setting, where models adapt to out-of-domain distributions without source data, leveraging test-time adaptation for robust bioactivity prediction.

Abstract: Accurate prediction of protein-ligand bioactivity is a cornerstone of modern drug discovery, yet current deep learning methods often struggle with out-of-domain (OOD) generalization. The existing methods rely on access to source data, making them impractical in scenarios where data cannot be accessed due to confidentiality, privacy concerns or intellectual property restrictions. In this paper, we provide the first exploration of a more realistic setting for bioactivity prediction, where models are expected to adapt to out-of-domain distributions without access to source data. Motivated by the critical role of binding-relevant interactions in determining ligand-protein bioactivity, we introduce an uncertainty-weighted consistency strategy, in which original samples with high confidence guide their augmented counterparts by minimizing feature distance. This encourages the model to focus on informative interaction regions while suppressing reliance on spurious or non-causal substructures. To further enhance representation discriminability and prevent feature collapse, we integrate a contrastive optimization objective that pulls together augmented views of the same complex and pushes away views from different complexes. Together, these two components enable the learning of invariant, bioactivity-aware representations, allowing robust adaptation under distribution shifts. Extensive experiments across DTIGN, SIU 0.6, and DrugOOD demonstrate that our framework consistently outperforms state-of-the-art baselines under scaffold, protein, and assay based OOD settings. Especially on the eight subsets of DTIGN, it improves Pearson’s $R$ by 8.2\% and Kendall’s Tau $\tau$ by 5.8\% on average over the best baseline, underscoring its effectiveness as a source data-absent solution for OOD bioactivity prediction.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 10932