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Counting on natural products for drug design

Abstract

Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.

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Figure 1: Rosuvastatin is a natural-product-inspired drug.
Figure 2: Natural products and their computationally generated fragments as inspiration for drug discovery.
Figure 3: Natural-product-inspired synthetic compounds with potent pharmacological effects.
Figure 4: Computer-assisted design of small molecules from natural product templates by scaffold simplification.
Figure 5: Fragment-based target identification with the SPiDER software.
Figure 6: Target predictions for natural products and synthetic bioactive molecules.

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Acknowledgements

We thank K.-H. Altmann for invaluable advice and discussion. This study was financially supported by the OPO Foundation, Zürich.

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Correspondence to Gisbert Schneider.

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P.S. and G.S. are the founders of inSili.com LLC, Zürich. All the other authors declare no competing financial interests.

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Rodrigues, T., Reker, D., Schneider, P. et al. Counting on natural products for drug design. Nature Chem 8, 531–541 (2016). https://doi.org/10.1038/nchem.2479

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