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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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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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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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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DOI: https://doi.org/10.1038/nchembio.188
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