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The re-emergence of natural products for drug discovery in the genomics era

Key Points

  • Natural products continue to be an important source of leads for new medicines, despite reduced interest from large pharmaceutical companies.

  • Screening collections of natural products can be assembled economically to provide excellent coverage of drug-like chemical space and in formats that are compatible with high-throughput bioassays.

  • Metabolomics enables the rapid identification of novel compounds in complex mixtures of natural products and also provides a means to monitor the production of target molecules during fermentation or other production processes.

  • Metagenomics and other genetic engineering techniques are enabling the production of target compounds in convenient systems, breaking away from the bottleneck otherwise created by microorganisms that are difficult to culture.

  • Examples of recent and current applications of natural products are described for the discovery of antimicrobials and for inhibitors of protein–protein interactions, particularly as anticancer agents.

Abstract

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein–protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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Figure 1: Biologically relevant chemical space is better covered by natural products than by synthetic compounds.
Figure 2: Metabolomics data workflow in natural product research.
Figure 3: Structures of biologically active natural products or natural-product-derived compounds.
Figure 4: Structures of artemisinic acid and artemisinin.

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Glossary

Chemical space

The multidimensional space occupied by all chemical compounds.

Pharmacophores

Molecules with atoms or chemical groups in a spatial arrangement known or predicted to be responsible for specific biological activity.

Stereochemistry

The spatial arrangement of atoms in a molecule.

Metabolomics

The systematic, qualitative and quantitative analysis of all metabolites contained or produced in an organism at a specific time and under specific conditions.

Metagenomics

The sequencing and analysis of DNA from environmental samples without the need for culturing individual clonal organisms.

Drug-like

Sharing certain characteristics — such as size, shape and solubility in water and organic solvents — with other molecules that act as drugs.

LogP

Logarithm of the octanol–water partition coefficient, which is a measure of a drug's lipophilicity. Defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Higher values imply greater lipophilicity.

Rule of five

A set of criteria, known collectively as Lipinski's 'rule of five', that identify several key properties that should be considered for compounds with oral delivery in mind. These properties are as follows: molecular mass < 500 Da, cLogP < 5, number of hydrogen-bond donors < 5 and number of hydrogen-bond acceptors < 10.

Dereplication

The process of using spectroscopic methods to identify known metabolites during the preliminary screening stage and eliminating further isolation work on already well-studied natural products.

One strain, many compounds

(OSMaC) An approach to activate metabolic pathways — by altering cultivation parameters, through co-cultivation or through the use of enzyme inhibitors or elicitors — that can be combined with genomics scanning.

Cryptic gene clusters

Genes that are normally not expressed (are 'silent') and do not translate into a phenotypic difference but that can become visible in a different environment to generate phenotypic diversity.

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Harvey, A., Edrada-Ebel, R. & Quinn, R. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov 14, 111–129 (2015). https://doi.org/10.1038/nrd4510

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