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 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.
Thorpe
D S
DS
Department of Discovery Biology, Selectide Corporation, Tucson, AZ 85737, USA. David.Thorpe@hmrag.com
Edith Chan
A W
AW
Binnie
A
A
Chen
L C
LC
Robinson
A
A
Spoonamore
J
J
Rodwell
D
D
Wade
S
S
Wilson
S
S
Ackerman-Berrier
M
M
Yeoman
H
H
Walle
S
S
Wu
Q
Q
Wertman
K F
KF
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
D004791:Enzyme Inhibitors; D008024:Ligands; D009711:Nucleotides; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D003958:Diamide; D011494:Protein Kinases; D010450:Endopeptidases