Biomimetic drug discovery

Natural products and their derivatives have long been a significant source of pharmaceuticals. A collection of articles in this Focus highlights efforts to mimic some aspects of the way in which these compounds are made in nature with the aim of improving the processes by which synthetic drug leads are identified.



Inspiration comes naturally p841


A collection of articles in this issue focuses on attempts to mimic aspects of natural-product biosynthesis for the identification of new drugs.

See also: Interview with Jeffrey Bode | Interview with Adam Nelson and Stuart Warriner | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode



Parallels with nature pp845 - 846

Interview with Adam Nelson and Stuart Warriner


Adam Nelson and Stuart Warriner, from the University of Leeds, talk with Nature Chemistry about their work to develop viable synthetic strategies for preparing new chemical structures in parallel with the identification of desirable biological activity.

See also: Editorial | Interview with Jeffrey Bode | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode

Public libraries pp846 - 847

Interview with Jeffrey Bode


Jeffrey Bode from ETH Zürich talks with Nature Chemistry about his group's work on synthetic fermentation, and how he hopes it could bring the power of chemical synthesis into the hands of citizen scientists.

See also: Editorial | Interview with Adam Nelson and Stuart Warriner | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode


News and Views

Drug discovery: Combichem all over again pp851 - 852

Derek B. Lowe


The generation of chemical libraries for screening is a key part of the drug discovery process. Now, two studies describe attempts to combine features of natural product biosynthesis into the creation of libraries with the aim of mimicking nature's success at the production of bioactive molecules.

See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | Article by Karageorgis et al. | Article by Huang & Bode



Efficient discovery of bioactive scaffolds by activity-directed synthesis pp872 - 876

George Karageorgis, Stuart Warriner & Adam Nelson


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A discovery approach termed activity-directed synthesis is described; it exploits arrays of reactions whose outcome is critically dependent on the conditions used, and prioritizes reactions that yield bioactive product mixtures. The discovery of both bioactive small molecules and associated synthetic routes thus occurs in parallel.

See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | News and Views by Lowe | Article by Huang & Bode

Synthetic fermentation of bioactive non-ribosomal peptides without organisms, enzymes or reagents pp877 - 884

Yi-Lin Huang & Jeffrey W. Bode


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The production of biologically active compounds by microbial fermentation has proved highly successful in drug discovery. Now, a method that mimics this process has been used to prepare unnatural peptides from small building blocks without the need for additional reagents, and in a fashion that is immediately compatible with biological screening.

See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | News and Views by Lowe | Article by Karageorgis et al.


From the archives

Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products pp735 - 740

Andrey P. Antonchick, Claas Gerding-Reimers, Mario Catarinella, Markus Schürmann, Hans Preut, Slava Ziegler, Daniel Rauh & Herbert Waldmann


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A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.

Subject terms: Medicinal chemistry | Chemical biology | Synthesis

Remodelling of the natural product fumagillol employing a reaction discovery approach pp969 - 973

Bradley R. Balthaser, Meghan C. Maloney, Aaron B. Beeler, John A. Porco, Jr & John K. Snyder


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The natural product fumagillol has been exploited as a stereochemically rich scaffold for the synthesis of a structurally unique, chemically diverse library with chemotypes distinctly different from the parent structure. Thus, fumagillol has been remodelled into a diverse array of isoindoles, isoquinolines, furans, mopholinones and benzoxazepines.

Subject terms: Organic chemistry | Synthesis

A biomimetic polyketide-inspired approach to small-molecule ligand discovery pp99 - 104

Claudio Aquino, Mohosin Sarkar, Michael J. Chalmers, Kimberly Mendes, Thomas Kodadek & Glenn C. Micalizio


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The design and synthesis of a family of chiral and conformationally constrained oligomers is described. Asymmetric synthesis of the monomers is presented and the preparation of a 160,000-member library of diverse tetramers via split-and-pool methods is discussed. From this library, a non-covalent ligand to the DNA-binding domain of p53 was discovered.

Subject terms: Chemical biology | Organic chemistry

See also: News and Views by Aubé

Small-molecule libraries: Naturally inspired oligomers pp71 - 72

Jeffrey Aubé


The design of a small-molecule library for drug discovery attempts to combine the favourable diversity of natural product structures with the modularity of peptide synthesis.

Subject terms: Organic chemistry | Medicinal chemistry

See also: Article by Aquino et al.

Natural-product-derived fragments for fragment-based ligand discovery pp21 - 28

Björn Over, Stefan Wetzel, Christian Grütter, Yasushi Nakai, Steffen Renner, Daniel Rauh & Herbert Waldmann


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Natural products populate areas of chemical space not occupied by average synthetic molecules. Here, an analysis of more than 180,000 natural product structures results in a library of 2,000 natural-product-derived fragments, which resemble the properties of the natural products themselves and give access to novel inhibitor chemotypes.

Subject terms: Chemical biology | Medicinal chemistry

See also: News and Views by Shoichet

Drug discovery: Nature's pieces pp9 - 10

Brian K. Shoichet


Natural products contain a range of chemical structures optimized for biological interactions. Fragmenting these compounds could help to combine this diversity with the broad coverage of chemical space offered by fragment-based drug discovery, and help to improve the efficiency with which screening hits can become successful drugs.

Subject terms: Medicinal chemistry | Theoretical chemistry

See also: Article by Over et al.

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products pp195 - 202

Robert W. Huigens III, Karen C. Morrison, Robert W. Hicklin, Timothy A. Flood Jr, Michelle F. Richter & Paul J. Hergenrother


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An approach for the construction of complex and diverse compound libraries is described, whereby natural products are altered through a series of ring system distortion reactions. The compounds produced have markedly different physiochemical properties from those in standard screening collections and thus could offer advantages in the search for lead molecules that can be developed into drug candidates.

Subject terms: Medicinal chemistry | Organic chemistry | Synthesis

See also: News and Views by Sharma & Tan

Drug discovery: Diversifying complexity pp157 - 158

Indrajeet Sharma & Derek S. Tan


A synthetic strategy that uses a series of simple reactions to distort the core architecture of complex natural products could provide libraries of stereochemically rich compounds that will help in the search for new biological probes and drugs.

Subject terms: Chemical biology | Medicinal chemistry | Organic chemistry

See also: Article by Huigens III et al.

A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling pp861 - 867

Henning S. G. Beckmann, Feilin Nie, Caroline E. Hagerman, Henrik Johansson, Yaw Sing Tan, David Wilcke & David R. Spring


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Diversity oriented synthesis (DOS) aims to build structurally diverse compound libraries — potentially useful in drug discovery — from a small number of starting materials. Here, the build/couple/pair algorithm — commonly used in DOS — is extended to incorporate variations in the coupling step as well as in the starting materials. This produces a compound library with exceptionally high diversity in fewer than five steps from a common precursor.

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids pp57 - 64

Haruki Mizoguchi, Hideaki Oikawa & Hiroki Oguri


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Emulating the biogenesis of natural products, a synthetic strategy is described in which an achiral multipotent intermediate reacts through three distinct [4 + 2] cyclizations and two types of redox-mediated annulation. This results in divergent access to natural product-like scaffolds in 6–9 steps. The efficiency of this approach is highlighted in the total syntheses of three natural products.

Probing chemical space with alkaloid-inspired libraries pp133 - 140

Michael C. McLeod, Gurpreet Singh, James N. Plampin, III, Digamber Rane, Jenna L. Wang, Victor W. Day & Jeffrey Aubé


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It has been suggested that bioactive natural products are an attractive starting point for the construction of screening libraries. Here, four families of biologically active alkaloids are used as the basis for the construction of 686 new compounds suitable for screening. The libraries thus prepared have characteristics comparable to representative natural products and are highly rule-of-five compliant.

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