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.