High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. 2009

Katherine H Sippel, and Arthur H Robbins, and John Domsic, and Caroli Genis, and Mavis Agbandje-McKenna, and Robert McKenna
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D002257 Carbonic Anhydrase Inhibitors A class of compounds that reduces the secretion of H+ ions by the proximal kidney tubule through inhibition of CARBONIC ANHYDRASES. Carbonate Dehydratase Inhibitor,Carbonate Dehydratase Inhibitors,Carbonic Anhydrase Inhibitor,Carboxyanhydrase Inhibitor,Carboxyanhydrase Inhibitors,Anhydrase Inhibitor, Carbonic,Dehydratase Inhibitor, Carbonate,Inhibitor, Carbonate Dehydratase,Inhibitor, Carbonic Anhydrase,Inhibitor, Carboxyanhydrase,Inhibitors, Carbonate Dehydratase,Inhibitors, Carbonic Anhydrase,Inhibitors, Carboxyanhydrase
D005990 Glycerol A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, or sweetening agent. 1,2,3-Propanetriol,Glycerin,1,2,3-Trihydroxypropane,Glycerine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000086 Acetazolamide One of the CARBONIC ANHYDRASE INHIBITORS that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. (From Smith and Reynard, Textbook of Pharmacology, 1991, p337) Acetadiazol,Acetazolam,Acetazolamide Sodium, (Sterile),Acetazolamide, Monosodium Salt,Ak-Zol,Apo-Acetazolamide,Diacarb,Diamox,Diuramide,Défiltran,Edemox,Glauconox,Glaupax,Huma-Zolamide,Ak Zol,AkZol,Apo Acetazolamide,ApoAcetazolamide,Huma Zolamide,HumaZolamide
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D020134 Catalytic Domain The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. Active Site,Catalytic Core,Catalytic Region,Catalytic Site,Catalytic Subunit,Reactive Site,Active Sites,Catalytic Cores,Catalytic Domains,Catalytic Regions,Catalytic Sites,Catalytic Subunits,Core, Catalytic,Cores, Catalytic,Domain, Catalytic,Domains, Catalytic,Reactive Sites,Region, Catalytic,Regions, Catalytic,Site, Active,Site, Catalytic,Site, Reactive,Sites, Active,Sites, Catalytic,Sites, Reactive,Subunit, Catalytic,Subunits, Catalytic
D024402 Carbonic Anhydrase II A cytosolic carbonic anhydrase isoenzyme found widely distributed in cells of almost all tissues. Deficiencies of carbonic anhydrase II produce a syndrome characterized by OSTEOPETROSIS, renal tubular acidosis (ACIDOSIS, RENAL TUBULAR) and cerebral calcification. EC 4.2.1.- Carbonic Anhydrase C,Carbonic Anhydrase Isoenzyme C

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