<p>Identification of drug-target interactions (DTIs) is critical for drug discovery and drug repositioning. However, most DTI methods that extract features from drug molecules and protein entities neglect specific substructure information of pharmacological responses, which leads to poor predictive performance. Moreover, most existing methods are based on molecular graphs or molecular descriptors to obtain abstract representations of molecules, but combining the two feature learning methods for DTI prediction remains unexplored. Therefore, a new ASCS-DTI framework for DTI prediction is proposed, which utilizes a substructure attention mechanism to flexibly capture substructures of compounds at different grain sizes, allowing the important substructure information of each molecule to be learned. Additionally, the framework combines three different molecular fingerprinting information to comprehensively characterize molecular representations. A stacked convolutional coding module processes the sequence information of target proteins in a multi-scale and multi-level view. Finally, multi-modal fusion of molecular graph features and molecular fingerprint features, along with multi-modal information encoding of DTIs, is performed by the feature fusion module. The method outperforms six advanced baseline models on different benchmark datasets: Biosnap, BindingDB, and Human, with a significant improvement in performance, particularly in maintaining strong results across different experimental settings.</p> Graphical Abstract <p></p>