Enhancing drug-target interaction prediction with graph representation learning and knowledge-based regularization

Introduction: Accurately predicting drug-target interactions (DTIs) is crucial for accelerating drug discovery and repurposing. Despite recent advances in deep learning-based methods, challenges remain in effectively capturing the complex relationships between drugs and targets while incorporating prior biological knowledge. Methods: We introduce a novel framework that combines graph neural networks with knowledge integration for DTI prediction. Our approach learns representations from molecular structures and protein sequences through a customized graph-based message passing scheme. We integrate domain knowledge from biomedical ontologies and databases using a knowledge-based regularization strategy to infuse biological context into the learned representations. Results: We evaluated our model on multiple benchmark datasets, achieving an average AUC of 0.98 and an average AUPR of 0.89, surpassing existing state-of-the-art methods by a considerable margin. Visualization of learned attention weights identified salient molecular substructures and protein motifs driving the predicted interactions, demonstrating model interpretability. Discussion: We validated the practical utility by predicting novel DTIs for FDA-approved drugs and experimentally confirming a high proportion of predictions. Our framework offers a powerful and interpretable solution for DTI prediction with the potential to substantially accelerate the identification of new drug candidates and therapeutic targets.