Efficient Discovery of Inhibitory Ligands for Diverse Targets from a Small Combinatorial Chemical Library of Chimeric Molecules

Living systems are mainly composed and regulated by compounds in four biochemical classes and their polymers—nucleotides, carbohydrates, lipids, and amino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical proper...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1999-12, Vol.266 (1), p.62-65
Main Authors: Thorpe, David S., Edith Chan, A.W., Binnie, Alan, Chen, L.Charlie, Robinson, Anna, Spoonamore, James, Rodwell, David, Wade, Shelly, Wilson, Sydney, Ackerman-Berrier, Martha, Yeoman, Helen, Walle, Stefan, Wu, Qinyuan (Quincey), Wertman, Kenneth F.
Format: Article
Language:English
Subjects:
amino acids
Binding Sites
Combinatorial Chemistry Techniques
Diamide - metabolism
Drug Evaluation, Preclinical - methods
Endopeptidases - metabolism
Enzyme Inhibitors - metabolism
Glycosylation
Hydrogen Bonding
Inhibitory Concentration 50
Ligands
Lipid Metabolism
Molecular Weight
nucleotides
Nucleotides - metabolism
Peptide Library
Protein Kinase Inhibitors
Protein Kinases - metabolism
Reproducibility of Results
Sensitivity and Specificity
Substrate Specificity
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Summary:Living systems are mainly composed and regulated by compounds in four biochemical classes and their polymers—nucleotides, carbohydrates, lipids, and amino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical properties of a combinatorial chemical library that used glyco, nucleotidyl, and lipid building blocks. The resulting chimeric combinatorial library of 361 compounds had a confirmed cumulative hit rate of 0.16%, which is 8-fold higher than a commonly claimed industrial benchmark of 0.02%. It produced 7 structurally confirmed hits for a third of 12 proprietary drug discovery projects, and these comprised a variety of molecular targets. Diversity analyses demonstrated that despite the small number of compounds, a wider range of diversity space was covered by this library of biochemical chimeras than by a branched tripeptide library of the same size and similar generic formula.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1999.1775