<p>Hyperparameter configuration.</p>

Drug-drug interactions (DDI) represent a significant clinical challenge in modern healthcare, contributing to over 125,000 deaths annually in the United States alone. Current computational approaches face substantial limitations in capturing long-range molecular dependencies and generalizing to novel drug combinations. Traditional Graph Neural Networks (GNNs) suffer from over-smoothing and locality bias, while sequence-based methods fail to adequately represent three-dimensional molecular structures. To address these limitations, we propose Graph Former-CL, a novel deep learning framework that synergistically combines Graph Transformer architecture with contrastive learning for DDI prediction. Our approach features four key innovations: (1) a hierarchical Graph Transformer with position-aware multi- head self-attention to capture both local and global molecular patterns, (2) a domain-specific contrastive learning module with molecular augmentation strategies, (3) a cross-modal fusion mechanism integrating SMILES sequences with graph representations, and (4) an adaptive pooling strategy for multi-scale molecular representation. Comprehensive evaluation on four benchmark datasets demonstrates superior performance, with Graph Former-CL achieving 98.2% accuracy on DrugBank and 89.4% on TWOSIDES, both representing statistically significant improvements (p < 0.001) over state-of-the-art methods. Notably, the framework achieves 85.6% accuracy for novel drugs in inductive settings, demonstrating robust generalization capabilities essential for real-world clinical applications.