Bioactivity-guided mapping and navigation of chemical space. Academic Article uri icon

start page

  • 585

end page

  • 592

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.

date/time value

  • 2009

Digital Object Identifier (DOI)

  • 10.1038/nchembio.188

PubMed Identifier

  • 19561619

volume

  • 5

number

  • 8

keywords

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