A comprehensive landscape of AI applications in broad-spectrum drug interaction prediction: a systematic review

In drug development, managing interactions such as drug–drug, drug–disease, and drug–nutrient is critical for ensuring the safety and efficacy of pharmacological treatments. These interactions often overlap, forming a complex, interconnected landscape that necessitates accurate prediction to improve patient outcomes and support evidence-based care. Recent advances in artificial intelligence (AI), powered by large-scale datasets (e.g., DrugBank, TWOSIDES, SIDER), have significantly enhanced interaction prediction. Machine learning, deep learning, and graph-based models show great promise, but challenges persist, including data imbalance, noisy sources, Limited explainability, and underrepresentation of certain types of interactions. This systematic review of 147 studies (2018–2024) is the first to comprehensively map AI applications across major interaction types. We present a detailed taxonomy of models and datasets, emphasizing the growing roles of large language models and knowledge graphs in overcoming key limitations. Their integration—alongside explainable AI tools—enhances transparency, paving the way for AI-driven systems that proactively mitigate adverse interactions. By identifying the most promising approaches and critical research gaps, this review lays the groundwork for advancing more robust, interpretable, and personalized models for drug interaction prediction.