Abstract
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
MeSH terms
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Animals
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Aurora Kinases
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Combinatorial Chemistry Techniques
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DNA / chemistry*
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DNA / genetics
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Drug Design*
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Models, Molecular
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Small Molecule Libraries / chemical synthesis*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Protein Kinase Inhibitors
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Small Molecule Libraries
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DNA
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Aurora Kinases
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
Associated data
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PDB/3HA6
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PDB/3HA8
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PubChem-Substance/81080197
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PubChem-Substance/81080198
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PubChem-Substance/81080199
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PubChem-Substance/81080200
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PubChem-Substance/81080201
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PubChem-Substance/81080202
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PubChem-Substance/81080203
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PubChem-Substance/81080204
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PubChem-Substance/81080205
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PubChem-Substance/81080206
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PubChem-Substance/81080207
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PubChem-Substance/81080208
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PubChem-Substance/81080209
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PubChem-Substance/81080210
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PubChem-Substance/81080211
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PubChem-Substance/81080212
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PubChem-Substance/81080213
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PubChem-Substance/81080214