AbstractMotivationProtein–ligand binding affinity prediction is a central task in drug design and development. Cross-modal attention mechanism has recently become a core component of many deep learning models due to its potential to improve model explainability. Non-covalent interactions (NCIs), one of the most critical domain knowledge in binding affinity prediction task, should be incorporated into protein–ligand attention mechanism for more explainable deep drug–target interaction models. We propose ArkDTA, a novel deep neural architecture for explainable binding affinity prediction guided by NCIs.ResultsExperimental results show that ArkDTA achieves predictive performance comparable to current state-of-the-art models while significantly improving model explainability. Qualitative investigation into our novel attention mechanism reveals that ArkDTA can identify potential regions for NCIs between candidate drug compounds and target proteins, as well as guiding internal operations of the model in a more interpretable and domain-aware manner.AvailabilityArkDTA is available athttps://github.com/dmis-lab/ArkDTAContactkangj@korea.ac.kr