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

Abstract

Fragment-based ligand and drug discovery predominantly employs sp2-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

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Figure 1: Fragment generation from the natural product Renieramycin P.
Figure 2: Filtering and clustering process.
Figure 3: Comparison of the chemical space defined by the natural product fragments and the chemical space represented by fragments derived from commercially available compounds.
Figure 4: Crystal structures of p38α MAP kinase in complex with natural-product-derived fragments.

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Acknowledgements

The research leading to these results was supported by funding from the European Research Council (ERC) under the European Union's Seventh Framework Program (FP7/ 2007-2013) and ERC grant agreement no. 268309, from the German Federal Ministry for Education and Research through the German National Genome Research Network-Plus (NGFN-Plus) (grant no. BMBF 01GS08104 to H.W. and D.R.), as well as from the Fonds der Chemischen Industrie.

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Contributions

B.O. and Y.N. performed computational experiments and syntheses. S.W. and S.R. performed computational experiments. B.O. performed biochemical experiments. B.O. and C.G. determined crystal structure analyses. B.O., S.W., D.R. and H.W. designed experiments. D.R. and H.W. supervised the research. B.O., S.W., D.R. and H.W. wrote the manuscript.

Corresponding author

Correspondence to Herbert Waldmann.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4921 kb)

Supplementary information

Representative natural product fragment library (PDF 6271 kb)

Supplementary information

Structure data file for representative natural product fragment library (SDF 2006 kb)

Supplementary information

Supplementary Table S1 - Summary of commercially available fragments (PDF 11016 kb)

Supplementary information

Structure data file for Supplementary Table S1 (SDF 1656 kb)

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Over, B., Wetzel, S., Grütter, C. et al. Natural-product-derived fragments for fragment-based ligand discovery. Nature Chem 5, 21–28 (2013). https://doi.org/10.1038/nchem.1506

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