title: Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules.
abstract: 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.
authors.affiliation: Department of Discovery Biology, Selectide Corporation, Tucson, AZ 85737, USA. David.Thorpe@hmrag.com
authors.forename: D S
authors.initials: DS
authors.lastname: Thorpe
authors.forename: A W
authors.initials: AW
authors.lastname: Edith Chan
authors.forename: A
authors.initials: A
authors.lastname: Binnie
authors.forename: L C
authors.initials: LC
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Robinson
authors.forename: J
authors.initials: J
authors.lastname: Spoonamore
authors.forename: D
authors.initials: D
authors.lastname: Rodwell
authors.forename: S
authors.initials: S
authors.lastname: Wade
authors.forename: S
authors.initials: S
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: Ackerman-Berrier
authors.forename: H
authors.initials: H
authors.lastname: Yeoman
authors.forename: S
authors.initials: S
authors.lastname: Walle
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: K F
authors.initials: KF
authors.lastname: Wertman
mesh_terms: D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003958:Diamide / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006031:Glycosylation; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008024:Ligands; D050356:Lipid Metabolism; D008970:Molecular Weight; D009711:Nucleotides / Q000378:metabolism*; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D009711:Nucleotides; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D003958:Diamide; D011494:Protein Kinases; D010450:Endopeptidases