Reverse fingerprinting, similarity searching by group fusion and fingerprint bit importance

Mol Divers. 2006 Aug;10(3):311-32. doi: 10.1007/s11030-006-9039-z. Epub 2006 Sep 21.

Abstract

Recent research has shown that using data fusion rules in fingerprint-based similarity searching can improve results over traditional searches. Group fusion scores, which use multiple reference compounds, have in particular been shown to be quite effective in increasing enrichment rates over single reference structure based searches. In this paper, the effectiveness of using data fusion with multiple reference compounds to increase similarity search recall rates was investigated using 44 biological targets and four different 2D fingerprinting systems, including a new 2D typed triangle fingerprinting system introduced here. Scaffold-hopping abilities using data fusion rules were investigated using eight (8) different classes of scaffolds active against cGMP phosphodiesterase isoform 5 (PDE5). An approach to using the reference group for ranking and visualizing important fingerprints bits, or reverse fingerprinting, was presented, and used to score and visualize important pharmacophore features within sample active molecules. Finally, similarity statistics within the reference groups were investigated and compared to recall rates.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / chemistry*
  • Chemical Phenomena
  • Chemistry, Pharmaceutical / methods*
  • Chemistry, Pharmaceutical / statistics & numerical data
  • Chemistry, Physical
  • Combinatorial Chemistry Techniques
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Databases, Factual / statistics & numerical data*
  • Databases, Factual / trends
  • Drug Design*
  • Humans
  • Models, Biological*
  • Molecular Structure
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Reference Values
  • Structure-Activity Relationship

Substances

  • Receptors, Cell Surface
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human