The Role of Natural Product Chemistry in Drug Discovery: Two Decades of Progress and Perspectives

Natural products (NPs) have long played a pivotal role in medicine, serving as both lead compounds and approved drugs in diverse therapeutic areas. Inspired by the 2004 review "The Role of Natural Product Chemistry in Drug Discovery", we adopted a data-driven approach to assess the current role of NPs in drug discovery. We identified 119 NP-derived (NP-D) drugs, including 16 antibody-drug conjugates (ADCs), that were first approved globally between January 2000 and September 2025. Their development timelines, source organisms, manufacturing methods, indications, and routes of administration were analyzed. Six NP-D case studies illustrating successful progression from discovery to clinical use were highlighted: omaveloxolone (novel pharmacology, first-in-class), fidaxomicin, ibrexafungerp, epoxomicin, eribulin (known pharmacology, new drug class), and the gliflozin drug family (13 members). We also examined the presence and sales of NP-D agents among the top 200 brand name drugs in 2006, 2015, and 2024. Although overall NP-D drug sales have declined, dapagliflozin and empagliflozin demonstrate that blockbuster status is still achievable. While growth is modest, NPs remain highly valuable active pharmaceutical ingredients (APIs) with substantial clinical impact. Significant opportunities persist for drug-focused NP R&D efforts, as many recently validated therapeutic targets remain underexplored for NP-D chemotypes.