MetaReact: A Reaction-Aware Transformer for End-to-End Prediction of Drug Metabolism

Abstract Accurate prediction of drug metabolites and enzyme selectivity is essential for rational drug design and safety assessment. However, existing computational approaches are often limited to specific enzyme families or reaction types, lacking the capacity to model enzyme-subtype specificity and prioritize major metabolites. Here, we present MetaReact, an end-to-end generalizable Transformer-based model that unifies the prediction of metabolic enzymes, metabolites, and sites of metabolism (SOM). By integrating structure-aware encoding ReactSeq, a chemistry reaction-based pretraining, MetaReact consistently outperforms state-of-the-art methods across multiple benchmarks under three settings: enzyme-agnostic, enzyme-completion, enzyme-conditioned. Notably, it achieves 60% Top-3 accuracy in identifying major metabolites and superior CYP450 enzyme-subtype prediction/SOM recognition. Case studies validate its applicability to complex natural products, synthetic cannabinoids, and clinical candidates, facilitating toxicity assessment and molecular optimization. This scalable, rule-free solution advances human metabolism modeling, with potential for computational pharmacokinetics and early drug discovery. Competing Interest Statement The authors have declared no competing interest. Footnotes Data availability The Drugbank data can be downloaded from https://go.drugbank.com/#. The MetXBioDB dataset is available at https://zenodo.org/records/4247792. The Recon3D dataset can be accessed at https://ngdc.cncb.ac.cn/databasecommons/database/id/6846. The HumanCyc dataset can be downloaded from the following link: https://maayanlab.cloud/Harmonizome/dataset/HumanCyc+Pathways. The SMPDB is available at https://smpdb.ca.