<p>Predicting drug-target binding affinity (DTA) is an important step in the complex process of drug discovery or drug repositioning. A large number of computational methods proposed for the task of DTA prediction utilize single features of proteins to measure drug-protein or protein-protein interactions, ignoring multi-feature fusion between protein-related features (e.g., solvent accessibility, protein pockets, secondary structures, and distance maps, etc.). To address the aforementioned constraints, we propose a new network topology and multi-feature fusion based approach for DTA prediction (NTMFF-DTA), which deeply mines protein multiple types of data and propagates drug information across domains. Data in drug-target interactions are often sparse, and multi-feature fusion can enrich data information by integrating multiple features, thus overcoming the data sparsity problem to some extent. The proposed approach offers two main contributions: (1) constructing a relationship-aware GAT that selectively focuses on the connections between nodes and edges in the molecular graph to capture the more central roles of nodes and edges in DTA prediction and (2) constructing an information propagation channel between different feature domains of drug proteins to achieve the sharing of the importance weight of drug atoms and edges, and combining with a multi-head self-attention mechanism to capture residue-enhancing features. The NTMFF-DTA model was comparatively tested against several leading baseline technologies on commonly used datasets. Experimental show that NTMFF-DTA can effectively and accurately predict DTA and outperform existing comparative models.</p> Graphical Abstract <p></p>