Abstract
Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Boronic Acids / chemical synthesis
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Boronic Acids / chemistry*
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Boronic Acids / metabolism
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Drug Design
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Endopeptidase Clp / antagonists & inhibitors*
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Endopeptidase Clp / metabolism
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Enzyme Assays
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Humans
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Peptide Library
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Peptidomimetics / chemical synthesis
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Peptidomimetics / chemistry*
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Peptidomimetics / metabolism
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Protein Binding
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Staphylococcus aureus / enzymology
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Stereoisomerism
Substances
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Boronic Acids
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Peptide Library
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Peptidomimetics
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ClpP protein, human
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Endopeptidase Clp
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CLPX protein, human