Abstract
We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aurora Kinases
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Binding Sites / drug effects
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Chemistry, Pharmaceutical / methods*
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Combinatorial Chemistry Techniques / methods*
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry*
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Ligands
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Mass Spectrometry / methods
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Models, Chemical
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Molecular Structure
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Purines / chemistry
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Ligands
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Purines
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Aurora Kinases
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Protein Serine-Threonine Kinases
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purine