Balancing focused combinatorial libraries based on multiple GPCR ligands

Farhad Soltanshahi, Tamsin E. Mansley, Sun Choi, Robert D. Clark

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists.

Original languageEnglish
Pages (from-to)529-538
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Issue number7-8
StatePublished - Aug 2006


  • ChemSpace
  • Combinatorial library
  • Library design
  • Multi-objective scoring
  • OptDesign
  • Pareto ranking


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