The Role of Natural Products in Modern Drug Discovery

Although historic discoveries may appear outdated, considering recent medical advances, various medications that were discovered from natural products continue to be used today.

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Nature's Medicine Chest

The discovery of penicillin in 1928, which is one of the most significant medical breakthroughs of the 20th century, was achieved following the observation that Penicillium mold released a substance that inhibited the growth of Staphylococcus bacteria.

In addition to penicillin, several other drugs still used in modern medicine were originally discovered from natural products, some of which include tetracycline, artemisinin, and doxorubicin2.

Natural products remain a cornerstone of modern drug discovery, with over 50% of current antibiotics derived from natural products. Some advantages of natural products include their higher molecular mass, diverse chemical nature, greater molecular rigidity,1 and unique spatial arrangements, including a greater number of sp3 carbon atoms and fewer nitrogen and halogen atoms.

For example, the higher rigidity of natural products can improve the ability to target protein-protein interactions.

Natural products also comprise numerous bioactive compounds associated with therapeutic benefits. However, the extraction and purification of these compounds are associated with many challenges, such as a loss of therapeutic efficacy.

Finding New Drugs from Nature

Historically, plant extracts were used as medications in their unpurified form, and little to no knowledge existed about which bioactive compounds within these plants were responsible for their therapeutic effects.

More recently, researchers have become increasingly interested in isolating the specific compounds from these plants to elucidate their biological mechanisms of action and identify compounds responsible for the plants’ desired therapeutic effects.

However, these efforts are associated with several challenges, as many of these compounds act synergistically with each other, and their isolation reduces or completely eliminates their therapeutic activities. To date, only a fraction of natural product compounds have been screened, thus necessitating the need for advanced high-throughput screening (HTS) assays to identify these compounds and assess their therapeutic activities.

Traditional cellular and molecular target-based HTS assays are often used to determine the potential of natural product libraries.

Recent advancements have also led to the use of novel technologies to screen natural products, some of which include microfabricated chips to identify antibiotic sensitivity, multi-omic analysis, virtual screening, combinatorial chemistry, fluidic and image-based technologies, phage display, antibody-based technology, and other biophysical approaches3.

Regardless of what assay is selected, an HTS assay must be highly robust in its performance and carefully designed to ensure appropriate target selection, orthogonal assays for hit validation, data analyses, and error management. Furthermore, combining these technologies with a systems biology approach may also advance innovative drug design and ultimately lead to the identification and development of superior drug candidates.

Learn more about Drug Discovery, Manufacturing and Development

Success Stories: Plants to Pharmaceuticals

Morphine, which was the first plant natural product, was originally isolated from Papaver somniferum or opium poppy in 1817 by German pharmacist Friedrich Serturner. Paclitaxel, which is a chemotherapy drug used to treat lung, ovarian, and breast cancers, was isolated from Tacus brevifolia, which is more commonly known as the Pacific yew.

The alkaloid quinine was isolated from the bark of Chinchona officinalis and eventually became the first effective medication against malaria. Salicinm, the active ingredient in aspirin responsible for its pain-relieving effects, was originally identified in the bark of Salix babylonica, otherwise known as the willow tree4.  

In addition to morphine, paclitaxel, and quinine, other plant-based bioactive compounds frequently used to treat human diseases include ginsenoside and artemisinin,, which are also anti-cancer and anti-malaria drugs, respectively4. In fact, about 25% of all drugs currently approved by the United States Food and Drug Administration (FDA) and European Medical Agency (EMA) are plant-based.

Natural products have typically originated from plants, invertebrates, bacteria, or other microorganisms. Marine organisms have also been heavily investigated as sources of bioactive natural compounds. In fact, over 37 patents from deep water products have been registered in both the U.S. and Europe, with at least 300 patents obtained on marine natural products5.

Prialt, for example, is the first medication to be approved by the U.S. FDA that was directly derived from marine natural products. This peptide toxin-conotoxin MVIIA ziconotide is indicated for pain management purposes.

Another marine natural product includes Trabectedin, which originates from the tunicate Ecteinascidia turbinate and received approval from the FDA in 2015 as an anti-cancer medication5.

Beyond the Ordinary: Nature's Unexplored Gems

The search for novel natural products with unique medicinal properties holds great potential for future medical breakthroughs. Classical natural product-based drug research is a multidisciplinary approach that integrates biology, chemistry, pharmacology, and environmental science.

Typically, this drug discovery process begins with the biological screening of crude extracts to identify a hit bioactive compound. Importantly, fractionation methods can be adjusted to select compounds with desired chemical characteristics, such as moderate hydrophilicity.

Various omics-based methods are also incorporated into this process.

Metabolomics, for example, can provide important information on the composition of natural product metabolites, which can allow researchers to prioritize certain compounds for isolation and further analysis4.

Some of the different methods that may be used for this type of metabolite profiling can include nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS), with or without the support of upstream liquid chromatography (LC) analysis.  

Challenges and the Future Outlook

The growing threat of antibiotic resistance, coupled with the continual emergence of novel diseases, such as the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, emphasizes the importance of exploring the potential of natural products for the discovery of innovative and effective drugs.

Recent technological advancements have allowed researchers to investigate the complex structural and chemical diversity of natural products while also assessing their therapeutic potential for a wide range of diseases.

These future endeavors must be accompanied by sustainable and ethical practices to ensure that both the global community and environments from which these natural products originate are preserved.

Thus, establishing the synergy between academia, industry, and indigenous communities will provide new opportunities for collaboration and offer unique insights into novel natural products needed to improve global public health. 

References

  1. Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., et al. (2021). Natural products in drug discovery: advances and opportunities. Nature Reviews Drug Discovery 20; 200-216. doi:10.1038/s41573-020-00114-z.
  2. Dzobo, K. (2022). The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Dsicovery. Comprehensive Pharmacology 408-422. doi:10.1016/B978-0-12-820472-6.00041-4.
  3. Ayon, N. J. (2023). High-Throughput Screening of Natural Product and Synthetic Molecule Libraries for Antibacterial Drug Discovery. Metabolites 13(5); 625. doi:10.3390/metabo13050625.
  4. Thomford, N. E., Senthebane, D. A., Rowe, A., et al. (2018). Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery. International Journal of Molecular Science 19(6); 1578. doi:10.3390/ijms19061578.
  5. Avhad, A. B., & Bhangale, C. J. (2023). Marine natural products and derivatives. RPS Pharmacy and Pharmacology Reports 2(2). doi:10.1093/rpsppr/rqad008.

Further Reading 

Last Updated: Jun 21, 2024

Benedette Cuffari

Written by

Benedette Cuffari

After completing her Bachelor of Science in Toxicology with two minors in Spanish and Chemistry in 2016, Benedette continued her studies to complete her Master of Science in Toxicology in May of 2018. During graduate school, Benedette investigated the dermatotoxicity of mechlorethamine and bendamustine; two nitrogen mustard alkylating agents that are used in anticancer therapy.

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