Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II 'selective' inhibitor celecoxib
Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II 'selective' inhibitor celecoxib(323 views) Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT
Bioorg Med Chem Lett Bioorganic And Medicinal Chemistry Letters (ISSN: 0960-894x), 2006 Jan 15; 16(2): 437-442.
Keywords: Acetazolamide, Carbonic Anhydrase, Celecoxib, Cox-2 Selective Inhibitors, Isoform Ii, Sulfonamide, Valdecoxib, X-Ray Crystallography, Analgesic Agent, Aromatic Compound, Benzene Derivative, Benzenesulfonamide Derivative, Carbonate Dehydratase Inhibitor, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitor, Diclofenamide, Dorzolamide, Functional Group, Glycine, Isoxazole, Isoxazole Derivative, Leucine, Methazolamide, Methyl Group, Proline, Threonine, Valine, Zinc Ion, Article, Chemical Bond, Chemical Interaction, Crystal Structure, Drug Design, Drug Potency, Drug Protein Binding, Enzyme Inhibition, Geometry, Hydrophobicity, Substitution Reaction, Binding Sites, Carbonic Anhydrase Inhibitors, Cyclooxygenase Inhibitors, Dna Topoisomerases, Type Ii, Drug Evaluation, Preclinical, Humans, Isoenzymes, Models, Molecular, Molecular Structure, Protein Conformation, Protein Structure, Tertiary, Pyrazoles, Structure-Activity Relationship,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy
Dipartimento Delle Scienze Biologiche-Sezione Biostrutture, University of Naples Federico II, via Mezzocannone 16, 80134 Naples, Italy
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy
Universit degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy
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Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II 'selective' inhibitor celecoxib
The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4. 2. 1. 1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn (II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Vall21, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Vall21, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi 1 angle of which is rotated of about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class. (c) 2005 Elsevier Ltd. All rights reserved
Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II 'selective' inhibitor celecoxib
Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II 'selective' inhibitor celecoxib