DPASyn: Mechanism-Aware Drug Synergy Prediction via Dual Attention and Precision-Aware Quantization

Abstract

Drug combinations are essential in cancer therapy, leveraging synergistic drug-drug interactions (DDI) to enhance efficacy and combat resistance. However, the vast combinatorial space makes experimental screening impractical, and existing computational models struggle to capture the complex, bidirectional nature of DDIs, often relying on independent drug encoding or simplistic fusion strategies that miss fine-grained inter-molecular dynamics. Moreover, state-of-the-art graph-based approaches suffer from high computational costs, limiting scalability for real-world drug discovery. To address this, we propose DPASyn, a novel drug synergy prediction framework featuring a dual-attention mechanism and Precision-Aware Quantization (PAQ). The dual-attention architecture jointly models intra-drug structures and inter-drug interactions via shared projections and cross-drug attention, enabling fine-grained, biologically plausible synergy modeling. While this enhanced expressiveness brings increased computational resource consumption, our proposed PAQ strategy complements it by dynamically optimizing numerical precision during training based on feature sensitivity-reducing memory usage by 40% and accelerating training threefold without sacrificing accuracy. With LayerNorm-stabilized residual connections for training stability, DPASyn outperforms seven state-of-the-art methods on the O'Neil dataset (13,243 combinations) and supports full-batch processing of up to 256 graphs on a single GPU, setting a new standard for efficient and expressive drug synergy prediction.