| Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue. | |
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MedLine Citation:
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PMID: 17125255 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The sulfamide analogue of the antiepileptic drug topiramate is a 210 times less potent inhibitor of isozyme II of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) compared to topiramate but effectively inhibits isozymes CA VA, VB, VII, XIII, and XIV (KI in the range of 21-35 nM). Its weak binding to CA II is due to a clash between one methyl group of the inhibitor and Ala65 and may be exploited for the drug design of compounds with lower affinity for this ubiquitous isozyme, as Ala65 is unique to CA II. As shown by X-ray crystallography, the sulfamide analogue binds to CA II with the deprotonated sulfamide moiety coordinated to Zn(II) and with the organic scaffold making an extended network of hydrogen bonds with Thr199, Gln92, His94, Asn62, and Thr200. Its binding to this isozyme is more similar to that of topiramate and quite different from that of the topiramate cyclic sulfate analogue RWJ-37947. |
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Authors:
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Jean-Yves Winum; Claudia Temperini; Khaled El Cheikh; Alessio Innocenti; Daniela Vullo; Samuele Ciattini; Jean-Louis Montero; Andrea Scozzafava; Claudiu T Supuran |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 49 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2006 Nov |
Date Detail:
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Created Date: 2006-11-27 Completed Date: 2007-02-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 7024-31 Citation Subset: IM |
Affiliation:
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Laboratoire de Chimie Biomoléculaire, UMR 5032, Ecole Nationale Supérieure de Chimie de Montpellier, Université Montpellier II, 8 Rue de l'Ecole Normale, 34296 Montpellier Cedex, France. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/2H15 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alanine
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chemistry* Anticonvulsants / chemistry Carbonic Anhydrase II / chemistry* Carbonic Anhydrase Inhibitors / chemical synthesis*, chemistry Crystallography, X-Ray Drug Design Fructose / analogs & derivatives*, chemical synthesis, chemistry Hydrogen Bonding Isoenzymes / chemistry Models, Molecular Molecular Structure Protein Binding Structure-Activity Relationship Sulfonamides / chemical synthesis*, chemistry |
| Chemical | |
Reg. No./Substance:
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0/Anticonvulsants; 0/Carbonic Anhydrase Inhibitors; 0/Isoenzymes; 0/Sulfonamides; 30237-26-4/Fructose; 56-41-7/Alanine; 97240-79-4/topiramate; EC 4.2.1.-/Carbonic Anhydrase II |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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