Abstract
Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, N.I.H., Extramural
MeSH terms
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Boronic Acids / chemistry*
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Crystallography, X-Ray
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Drug Evaluation, Preclinical / methods
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Humans
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Nitriles / chemistry
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / genetics
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Phosphoric Diester Hydrolases / metabolism*
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Serine Endopeptidases / metabolism
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship*
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Surface Plasmon Resonance
Substances
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Boronic Acids
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Nitriles
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Serine Proteinase Inhibitors
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Small Molecule Libraries
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Phosphoric Diester Hydrolases
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alkylglycerophosphoethanolamine phosphodiesterase
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Serine Endopeptidases