Abstract
Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Bicyclic Monoterpenes
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Binding Sites
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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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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Fibrinolysin / metabolism
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Fibrinolytic Agents / chemical synthesis
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / metabolism
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Humans
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Kinetics
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Ligands
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Models, Molecular
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Protein Binding
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Structure-Activity Relationship
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Terpenes / chemical synthesis
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Terpenes / chemistry
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Thrombin / antagonists & inhibitors*
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Trypsin / metabolism
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Urea / chemical synthesis
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Urea / chemistry
Substances
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Amides
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Bicyclic Monoterpenes
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Boronic Acids
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Enzyme Inhibitors
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Fibrinolytic Agents
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Ligands
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Terpenes
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pinane
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Urea
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Trypsin
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Thrombin
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Fibrinolysin