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| - | [[Image:1oq5.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1oq5| PDB=1oq5 | SCENE= }} | | {{STRUCTURE_1oq5| PDB=1oq5 | SCENE= }} |
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| - | '''CARBONIC ANHYDRASE II IN COMPLEX WITH NANOMOLAR INHIBITOR'''
| + | ===CARBONIC ANHYDRASE II IN COMPLEX WITH NANOMOLAR INHIBITOR=== |
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| - | ==Overview==
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| - | By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_14736236}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 14736236 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_14736236}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: 10-stranded]] | | [[Category: 10-stranded]] |
| | [[Category: Twisted beta-sheet]] | | [[Category: Twisted beta-sheet]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 04:08:57 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 13:48:59 2008'' |
Revision as of 10:49, 28 July 2008
Template:STRUCTURE 1oq5
CARBONIC ANHYDRASE II IN COMPLEX WITH NANOMOLAR INHIBITOR
Template:ABSTRACT PUBMED 14736236
About this Structure
1OQ5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition., Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G, J Med Chem. 2004 Jan 29;47(3):550-7. PMID:14736236
Page seeded by OCA on Mon Jul 28 13:48:59 2008
