Context <p>Accurate prediction of drug-target affinity (DTA) is crucial for accelerating drug discovery, but it remains a significant challenge. While deep learning methods have shown promise, many existing models struggle with representing long-range protein relationships within protein–protein interaction (PPI) networks, often suffering from performance degradation as graph neural network layers deepen. To overcome this limitation, we developed HopWD-DTA, a novel framework designed to effectively capture both local and global protein features. The core innovation lies in integrating multi-hop neighborhood information from PPI networks with deep structural features of proteins and drugs. Comprehensive evaluations on the Davis, KIBA, and Human benchmark datasets demonstrate that HopWD-DTA achieves state-of-the-art performance, significantly improving DTA prediction accuracy over existing cutting-edge solutions.</p> Methods <p>The HopWD-DTA framework consists of separate branches for protein and drug feature extraction. For proteins, structural features from residue contact maps are first encoded using a Graph Convolutional Network (GCN). These features, along with InterPro annotations, are then embedded into a PPI network. We introduce a multi-hop neighborhood serialization technique, which generates a sequence of feature matrices representing different neighborhood scopes. This sequence is processed by a Variational Autoencoder (VAE) to learn a robust protein representation. For drugs, molecules are represented as graphs from SMILES strings and encoded via a GCN, followed by a novel Wide-and-Deep Path (WDPATH) module to capture both macroscopic and microscopic features. The final protein and drug features are concatenated and fed into a multilayer perceptron for affinity prediction. The model was implemented using PyTorch and RDKit.</p>