Language model-guided anticipation and discovery of mammalian metabolites

Despite decades of study, large parts of the mammalian metabolome remain unexplored1. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks in human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains challenging2–4. Biochemical language models have transformed the interpretation of DNA, RNA and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here we present an approach that leverages chemical language models5–7 to anticipate the existence of previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns from the structures of known metabolites to anticipate the existence of previously unrecognized metabolites. Integration of DeepMet with mass spectrometry-based metabolomics data facilitates metabolite discovery. We harness DeepMet to reveal several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to advance the mapping of the mammalian metabolome. Chemical language models trained on known metabolites can identify previously unknown metabolites from mass spectrometry-based metabolomics data with high accuracy.