HKD-CPI: high-order knowledge distillation enhanced inductive compound-protein interaction prediction

<h4>Motivation</h4>Accurately identifying compound-protein interactions (CPIs) is critical for accelerating drug discovery. Recent deep learning methods have achieved impressive results, yet they primarily focus on local structures and neighborhood information, often overlooking high-order interaction patterns shared among similar molecules.<h4>Results</h4>In this paper, we propose HKD-CPI, a high-order knowledge-enhanced inductive framework designed to improve generalization to unseen compound-protein pairs. Specifically, HKD-CPI introduces a molecular graph tokenization mechanism that aligns compound molecular graph features with token embeddings from sequence-pretrained large language models (LLMs), effectively infusing sequence-derived semantics into structural representations. To capture shared interaction patterns among functionally similar biomolecules, we construct a hypergraph-based representation to model high-order relationships between feature-similar compound/protein groups and their binding partners. Furthermore, a knowledge distillation strategy is further adopted to transfer high-order interaction knowledge from the hypergraph to a lightweight student model, enabling efficient and robust CPI prediction. Extensive experiments demonstrate that HKD-CPI outperforms existing state-of-the-art methods in inductive CPI prediction tasks. In particular, it achieves an average improvement of 4.94% in AUROC and 3.64% in AUPRC over the best-performing baseline across five benchmark datasets.<h4>Availability and implementation</h4>Our code and data are available at https://github.com/Hezy618/HKD-CPI.