The evolving role of natural products in drug discovery

Key Points

  • Chemical substances derived from animals, plants and microbes have been a major source of lead compounds for the pharmaceutical industry; of the 877 small-molecule New Chemical Entities (NCEs) introduced between 1981 and 2002, 49% were natural products, semi-synthetic natural product analogues or synthetic compounds based on natural-product pharmacophores.

  • Despite this success, pharmaceutical research into natural products has experienced a slow decline during the past two decades.

  • The decreased emphasis in the pharmaceutical industry on the discovery of natural products can be attributed to several factors, including:

  • the introduction of high-throughput screening against defined molecular targets, which prompted many companies to move from natural-product extract libraries towards 'screen friendly' synthetic chemical libraries.

  • the development of combinatorial chemistry, which at first offered the prospect of simpler, more drug-like screening libraries of wide chemical diversity

  • advances in molecular biology, cellular biology and genomics, which increased the number of molecular targets and prompted shorter drug discovery timelines.

  • However, emerging trends, coupled with unrealized expectations from current R&D strategies, are prompting a renewed interest in natural products as a source of chemical diversity and lead generation. As reviewed here, technological advances, in particular, crucial breakthroughs in separation and structure-determination technologies, are addressing the factors above that led to decreased pharmaceutical research into natural products.


Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

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Figure 1: Worldwide pharmaceutical natural-product patents.
Figure 2: Examples of natural-product drugs.
Figure 3: Structural themes in natural products that target tubulin protein–protein interactions.
Figure 4: Using natural-product structure–activity relationships and shotgun synthesis to optimize biological activity: the example of mannopeptimycins.
Figure 5: Chemical process for natural product discovery.
Figure 6: Generic scheme for bioassay-guided fractionation.
Figure 7: Affinity-based identification system for natural products.
Figure 8: Harnessing highly toxic natural products for cancer therapy.


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Entrez Gene





The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.


(NME). A medication containing an active ingredient that has not been previously approved for marketing in any form.


The generation of large collections, or 'libraries', of compounds by synthesizing combinations of a set of smaller chemical structures.


Sharing certain characteristics with other molecules that act as drugs. The set of characteristics — size, shape and solubility in water and organic solvents — varies depending on who is evaluating the molecules.


Lipinski's analysis of the World Drug Index led to the 'rule-of-five', which identifies several key properties that should be considered for small molecules that are intended to be orally administered. These properties are: molecular mass <500 Da, number of hydrogen-bond donors <5; number of hydrogen-bond acceptors <10; calculated octanol–water partition coefficient (an indication of the ability of a molecules to cross biological membranes) <5.


The total repertoire of three-dimensional protein structures or architectures.


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A method of reducing test-compound interference in fluorescence-based screening by rejection of signals from short-lifetime sources.

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Koehn, F., Carter, G. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4, 206–220 (2005).

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