Instructions for nature's LEGO Bricks

​This Behind the paper Highlight is in reference to our paper in Nature Chemistry: "Principle and design of pseudo-natural products" DOI: 10.1038/s41557-019-0411-x

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Our lab addresses the fundamental question how novel bioactive compounds can be designed and synthesised. We take inspiration from Nature and the small molecules it generates in evolution and try to capture the structural principles underlying their biological activity and relevance in new design principles. This led to Biology Oriented Synthesis (BIOS) of compound classes with natural product inspired structure. In an intellectual leap we now go beyond the structures generated by nature and embrace the principle of fragment based compound design to arrive at “pseudo natural products” (pseudo NPs) which derive from alternative combinations of fragments occurring in natural products – similar to connecting LEGO bricks in different ways (Figure 1). Pseudo NPs retain the biological relevance of NPs, yet exhibit novel structures not accessible to nature through existing biosynthesis pathways and promise to show novel bioactivity. We had demonstrated successful applications of this concept with the Chromopynones,[1] Indomorphans,[2] Indotropanes,[3] as well as Pyranofuropyridones.[4] In the Concept paper we now outline the general principle and design approach. 

Figure 1: Recombining Natural Product derived fragments yields novel scaffolds termed Pseudo-Natural Products. Read our full paper outlining how to connect them.

A comparative cheminformatic analysis of pseudo-NPs, BIOS compounds, and approved drugs, demonstrated that pseudo-NPs may have favourable properties, such as molecular weight, lipophilicity, or shape diversity by design. We identified certain connectivity patterns between the distinct fragments which allow the classification of pseudo-NPs, and derived a set of first principles which can be used to design novel pseudo-NP classes in a consistent and methodical manner. To demonstrate the generality of these principles, we designed novel pseudo-NP classes using either the pyrrolidine and tropane fragments, or the pyrrolidine and tetrahydroquinoline fragments. Connecting the individual fragments using different patterns, yields compound classes with distinct profiles, allowing the rapid exploration of biologically relevant chemical space. 

Compound classes reported earlier retrospectively can be classed as pseudo-NPs which shows that the scientific community has explored some of these structures, yet not in a consistent manner. The Concept paper provides the scientific community a recipe of sorts for pseudo-NP design, and hence a kind of road-map for the exploration of chemical space which these structures cover. Chemists are very creative in developing new methodologies for synthesis, yet their application towards the preparation of biologically relevant compounds can prove challenging at times. Pseudo-NPs may require this high level of creativity for their preparation, which can be offset by their a priori biological relevance.

To take full advantage of the biological relevance of pseudo-NPs, wider screening campaigns and subsequent target identification methods may be required. The recent emergence of multiparametric screening platforms such as the ‘cell painting assay’ and new target identification/validation methodologies such as thermal-shift assays and target degradation assays provide opportunities to realise the full value of pseudo-NPs. We expect that this Concept paper will open new opportunities for molecular discovery in chemical biology research. 

References:

[1] Nature Chem. 2018, 10, 1103

[2] Angew. Chem. Int. Ed., 2019, 58, 17016

[3] Cell Chem Biol., 2019, 26, 512

[4] Angew. Chem. Int. Ed., 2019, 58, 14715

George Karageorgis

Postdoctoral Fellow, MPI-Dortmund

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