Article abstract


Nature Chemical Biology 5, 585 - 592 (2009)
Published online: 28 June 2009 | doi:10.1038/nchembio.188

Bioactivity-guided mapping and navigation of chemical space

Steffen Renner1,2,9, Willem A L van Otterlo1,3, Marta Dominguez Seoane4, Sabine Möcklinghoff4, Bettina Hofmann5, Stefan Wetzel1,2, Ansgar Schuffenhauer6, Peter Ertl6, Tudor I Oprea7, Dieter Steinhilber5, Luc Brunsveld4,8, Daniel Rauh4 & Herbert Waldmann1,2


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 ERalpha.

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  1. Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund, Germany.
  2. Technische Universität Dortmund, Fakultät Chemie, Dortmund, Germany.
  3. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa.
  4. Chemical Genomics Centre of the Max-Planck-Society, Dortmund, Germany.
  5. Institute of Pharmaceutical Chemistry, Center for Drug Research, Development and Safety, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
  6. Novartis Institutes for BioMedical Research, Basel, Switzerland.
  7. Division of Biocomputing, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
  8. Technische Universiteit Eindhoven, Department of Biomedical Engineering, Eindhoven, the Netherlands.
  9. Present address: Novartis AG, Novartis Institutes for BioMedical Research, Basel, Switzerland.

Correspondence to: Herbert Waldmann1,2 e-mail: herbert.waldmann@mpi-dortmund.mpg.de



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