Machine Learning-Based Bioactivity Classification of Natural Products Using LC-MS/MS Metabolomics

The rediscovery of known drug classes represents a major challenge in natural products drug discovery. Compound rediscovery inhibits the ability of researchers to explore novel natural products and wastes significant amounts of time and resources. This study introduces a novel machine learning framework that can effectively characterize the bioactivity of natural products by leveraging liquid chromatography tandem mass spectrometry and untargeted metabolomics analysis. This accelerates natural product drug discovery by addressing the challenge of dereplicating previously discovered bioactive compounds. Utilizing the SIRIUS 5 metabolomics software suite and in-silico-generated fragmentation spectra, we have trained a ML model capable of predicting a compound's drug class. This approach enables the rapid identification of bioactive scaffolds from LC-MS/MS data, even without reference experimental spectra. The model was trained on a diverse set of molecular fingerprints generated by SIRIUS 5 to effectively classify compounds based on their core pharmacophores. Our model robustly classified 21 diverse bioactive drug classes, achieving accuracies greater than 93% on experimental spectra. This study underscores the potential of ML combined with MFPs to dereplicate bioactive natural products based on pharmacophore, streamlining the discovery process and expediting improved methods of isolating novel antibacterial and antifungal agents.