Bridging Bioassay-Guided Isolation and Metabolomics: Toward Hybrid Strategies in Natural Product Drug Discovery

Natural products (NPs) remain an important source of drug discovery, providing approximately 32% of newly introduced small molecule drugs between 1981 to 2019. The identification and isolation of bioactive compounds from natural product presents both great opportunities and challenges even for modern pharmaceutical research. Two primary approaches have emerged as dominant methodologies: the traditional bioassay-guided isolation (BGI) and the more recent metabolomics-based discovery approaches. This comprehensive review critically compares these methodologies, including their principles, technical capabilities, strengths, limitations, and their applications in natural product discovery. While BGI has a long history as the gold standard, providing remarkable drugs such as artemisinin, paclitaxel, and vinblastine, metabolomics offers broad chemical coverage, sensitivity, and high throughput capabilities that can overcome the limitations of activity-driven approaches. To accelerate, improve the accuracy and ensure the success of natural product–based research, selecting only one of the two approaches is not advisable. This review recommends combining both approaches to leverage the strengths of each while addressing their respective limitations, thereby enhancing the success of natural product drug discovery research. In this context, metabolomics provides accurate data for compound prioritization from the phytochemical complexity of NPs, whereas BGI delivers precise data for confirming active compounds and verifying bioactivity. By adopting this hybrid method, the research timeline for natural product–based drug discovery can be accelerated and more accurate.