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Bioactivity-guided mapping and navigation of chemical space

Nature Chemical Biology volume 5, pages 585–592 (2009)Cite this article

Abstract

The structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements provides a valid, intuitive means to map and navigate chemical space. We demonstrate that scaffold trees built using bioactivity as the key selection criterion for structural simplification during tree construction allow efficient and intuitive mapping, visualization and navigation of the chemical space defined by a given library, which in turn allows correlation of this chemical space with the investigated bioactivity and further compound design. Brachiation along the branches of such trees from structurally complex to simple scaffolds with retained yet varying bioactivity is feasible at high frequency for the five major pharmaceutically relevant target classes and allows for the identification of new inhibitor types for a given target. We provide proof of principle by identifying new active scaffolds for 5-lipoxygenase and the estrogen receptor ERα.

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Figure 1: Bioactivity-guided construction of a scaffold tree exemplified for paclitaxel-derived tubulin stabilizers and indole alkaloids active on the 5-hydroxytryptamine receptor 5HT-2A.
Figure 2: Selected examples of identified scaffold branches.
Figure 3: Brachiation within major target classes.
Figure 4: Distribution of brachiation length and size (number of rings in the largest scaffold) of the scaffolds.
Figure 5: Brachiation-based identification of new active scaffolds for 5-lipoxygenase and for ERα.

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Acknowledgements

This research was supported by the Max-Planck-Gesellschaft and the Fonds der Chemischen Industrie. Part of this work was supported by US National Institutes of Health grants 1R01CA127731 and 1U54MH084690 (to T.I.O.) and by the German Federal Ministry for Education and Research through the German National Genome Research Network-Plus (grant number BMBF 01GS08102, to D.R. and H.W.). W.A.L.v.O. thanks the Alexander von Humboldt Foundation for a Georg Forster Research Fellowship for Experienced Researchers.

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  1. Steffen Renner

    Present address: Present address: Novartis AG, Novartis Institutes for BioMedical Research, Basel, Switzerland.,

Authors and Affiliations

  1. Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany

    Steffen Renner, Willem A L van Otterlo, Stefan Wetzel & Herbert Waldmann

  2. Technische Universität Dortmund, Fakultät Chemie, Dortmund, Germany

    Steffen Renner, Stefan Wetzel & Herbert Waldmann

  3. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa

    Willem A L van Otterlo

  4. Chemical Genomics Centre of the Max-Planck-Society, Dortmund, Germany

    Marta Dominguez Seoane, Sabine Möcklinghoff, Luc Brunsveld & Daniel Rauh

  5. Institute of Pharmaceutical Chemistry, Center for Drug Research, Development and Safety, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

    Bettina Hofmann & Dieter Steinhilber

  6. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Ansgar Schuffenhauer & Peter Ertl

  7. Division of Biocomputing, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA

    Tudor I Oprea

  8. Department of Biomedical Engineering, Technische Universiteit Eindhoven, Eindhoven, the Netherlands

    Luc Brunsveld

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Correspondence to Herbert Waldmann.

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Competing interests

T.I.O. is the owner of Sunset Molecular, the distributor of the WOMBAT database that we used in our studies.

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Supplementary Figures 1–5 and Supplementary Methods (PDF 638 kb)

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Renner, S., van Otterlo, W., Dominguez Seoane, M. et al. Bioactivity-guided mapping and navigation of chemical space. Nat Chem Biol 5, 585–592 (2009). https://doi.org/10.1038/nchembio.188

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