Bioactivity-guided mapping and navigation of chemical space

Nat Chem Biol. 2009 Aug;5(8):585-92. doi: 10.1038/nchembio.188. Epub 2009 Jun 28.

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 ERalpha.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / chemistry
  • Chemistry, Pharmaceutical / methods*
  • Computer Simulation*
  • Databases, Factual*
  • Estrogen Receptor alpha / chemistry
  • Models, Molecular*
  • Protein Binding
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Software*
  • Structure-Activity Relationship

Substances

  • Estrogen Receptor alpha
  • Small Molecule Libraries
  • Arachidonate 5-Lipoxygenase

Associated data

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