1OQ5

CARBONIC ANHYDRASE II IN COMPLEX WITH NANOMOLAR INHIBITOR

1OQ5 の概要

• エントリーDOI: 10.2210/pdb1oq5/pdb
• 関連するPDBエントリー: 1CIL
• 分子名称: Carbonic anhydrase II, ZINC ION, 4-[5-(4-METHYLPHENYL)-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL]BENZENESULFONAMIDE, ... (4 entities in total)
• 機能のキーワード: 10-stranded, twisted beta-sheet, metal binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29604.64

構造登録者

Weber, A.,Casini, A.,Heine, A.,Kuhn, D.,Supuran, C.T.,Scozzafava, A.,Klebe, G. (登録日: 2003-03-07, 公開日: 2004-03-23, 最終更新日: 2023-08-16)

主引用文献

Weber, A.,Casini, A.,Heine, A.,Kuhn, D.,Supuran, C.T.,Scozzafava, A.,Klebe, G.
Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.
J.Med.Chem., 47:550-557, 2004

PubMed Abstract: 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.

PubMed: 14736236
DOI: 10.1021/jm030912m

実験手法

X-RAY DIFFRACTION (1.5 Å)