Natural products have been the most productive source of drugs in human medicine. Over half of approved drugs are derived from or inspired by natural products. The chemical diversity of natural products exceeds synthetic compound libraries, with complex scaffolds, multiple stereocenters, and extensive functionalization that occupy regions of chemical space not accessible by synthetic chemistry.
Major sources include microorganisms, plants, and marine organisms. Actinobacteria, particularly Streptomyces species, have produced most microbial natural product drugs including antibiotics, antifungals, immunosuppressants, and anticancer agents. The golden age of antibiotic discovery from soil microorganisms yielded streptomycin, tetracycline, chloramphenicol, and erythromycin.
Plant natural products include the anticancer drug paclitaxel from Taxus brevifolia, the antimalarial artemisinin from Artemisia annua, the analgesic morphine from Papaver somniferum, and the cardiovascular drug digoxin from Digitalis purpurea. Traditional medicine systems provide ethnobotanical leads for drug discovery programs.
Marine natural products have emerged as a rich source of novel chemical structures. Sponges, tunicates, mollusks, and marine microorganisms produce compounds with anticancer and anti-inflammatory activity. Approved marine-derived drugs include trabectedin from the tunicate Ecteinascidia turbinata and eribulin from the sponge Halichondria okadai.
The drug discovery process begins with collection of biological material, extraction, bioassay-guided fractionation, and structural elucidation. Dereplication using LC-MS and NMR databases identifies known compounds early to avoid redundant characterization. High-throughput screening of natural product extracts against disease-relevant targets identifies active fractions for purification.
Advances in genomics have revitalized natural product discovery. Genome sequencing reveals biosynthetic gene clusters encoding polyketide synthases, non-ribosomal peptide synthetases, and terpene cyclases. Heterologous expression and genome mining activate silent gene clusters to produce new compounds. Synthetic biology enables pathway engineering for improved yields and analog production.
Challenges include supply sustainability, rediscovery of known compounds, and the complexity of natural product synthesis. Strategies include semi-synthesis, total synthesis, and combinatorial biosynthesis to generate analogs with improved properties.
