From Detection to Mechanism: Cross-Attention Graph Neural Networks Enable Drug-Drug Interaction Type Prediction An Ablation Study with Acetylsalicylic Acid Validation

Abstract

Predicting whether two drugs interact (binary detection) is a substantially dif- ferent task from predicting the mechanism type of that interaction (multi-class classification). This study presents a systematic ablation study of three Graph Neural Network (GNN) architectures for drug-drug interaction (DDI) prediction on a publicly available benchmark dataset comprising 38,337 positive pairs across 86 interaction types. Three architectures are compared under identical training conditions (n = 61,339 pairs): a siamese dual Message Passing Neural Network (MPNN) with concatenation (Concat), a dual MPNN with four-head cross-attention (CrossAtt), and a ternary MPNN incorporating an interaction graph (Ternary). CrossAtt improves multi-class F1-macro by +0.186 absolute (+45%) over Concat, while improving binary AUC by only +0.012 (+1.3%) - confirming that atom-level inter-molecular communication specifically enables mechanism-type classification. The ternary architecture underperforms despite equivalent training data, with its failure consistent with a training instability hypothesis. Validation on ten acetylsali- cylic acid (ASA) drug pairs, held out prior to training, demonstrates 10/10 correct DDI-type predictions for CrossAtt versus 0/10 for Ternary. Two consistent failure cases are identified across all architectures, linking to structural limits established in a companion toxicity study.