Active site ring-opening of a thiirane moiety and picomolar inhibition of gelatinases
| Autor: | Marta Toth, Qicun Shi, Mijoon Lee, Shahriar Mobashery, Christopher C. Forbes, Jed F. Fisher, Rafael Fridman, Leticia I. Llarrull, Michael Gossing, Dusan Hesek |
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| Rok vydání: | 2009 |
| Předmět: |
Gelatinases
Stereochemistry Matrix metalloproteinase inhibitor Stereoisomerism Matrix metalloproteinase Matrix Metalloproteinase Inhibitors Molecular Dynamics Simulation Biochemistry Article chemistry.chemical_compound Heterocyclic Compounds 1-Ring Deprotonation Catalytic Domain Drug Discovery Moiety Sulfones Enzyme Inhibitors Pharmacology biology Organic Chemistry Active site Kinetics Zinc Thiirane chemistry biology.protein Molecular Medicine Matrix Metalloproteinase 2 |
| Zdroj: | Chemical biologydrug design. 74(6) |
| ISSN: | 1747-0285 |
| Popis: | (+/-)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable K(i) of 530 pm against matrix metalloproteinase-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases. |
| Databáze: | OpenAIRE |
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