Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules |
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Authors: | Thorpe D S Edith Chan A W Binnie A Chen L C Robinson A Spoonamore J Rodwell D Wade S Wilson S Ackerman-Berrier M Yeoman H Walle S Wu Q Wertman K F |
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Affiliation: | Department of Discovery Biology, Selectide Corporation, Tucson, AZ 85737, USA. David.Thorpe@hmrag.com |
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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. |
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