Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies.
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De Simone G, Di Fiore A, Menchise V, Pedone C, Antel J, Casini A, Scozzafava A, Wurl M, Supuran CT
Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies.
Bioorg Med Chem Lett. 2005 May 2;15(9):2315-20.
- PubMed ID
- 15837316 [ View in PubMed]
- Abstract
The antiepileptic drug zonisamide was considered to act as a weak inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) (with a K(I) of 4.3 microM against the cytosolic isozyme II). Here we prove that this is not true. Indeed, testing zonisamide in the classical assay conditions of the CO2 hydrase activity of hCA II, with incubation times of enzyme and inhibitor solution of 15 min, a K(I) of 10.3 microM has been obtained. However, when the incubation between enzyme and inhibitor was prolonged to 1 h, the obtained K(I) was of 35.2 nM, of the same order of magnitude as that of the clinically used sulfonamides/sulfamates acetazolamide, methazolamide, ethoxzolamide and topiramate (K(I)s in the range of 5.4-15.4 nM). The inhibition of the human mitochondrial isozyme hCA V with these compounds has been also tested by means of a dansylamide competition binding assay, which showed zonisamide and topiramate to be effective inhibitors, with K(I)s in the range of 20.6-25.4 nM. The X-ray crystal structure of the adduct of hCA II with zonisamide has also been solved at a resolution of 1.70 A, showing that the sulfonamide moiety participates in the classical interactions with the Zn(II) ion and the residues Thr199 and Glu106, whereas the benzisoxazole ring is oriented toward the hydrophobic half of the active site, establishing a large number of strong van der Waals interactions (<4.5 A) with residues Gln92, Val121, Phe131, Leu198, Thr200, Pro202.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Zonisamide Carbonic anhydrase 1 Protein Humans UnknownInhibitorDetails Zonisamide Carbonic anhydrase 2 Protein Humans UnknownInhibitorDetails Zonisamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Zonisamide Carbonic anhydrase 4 Protein Humans UnknownInhibitorDetails Zonisamide Carbonic anhydrase 5A, mitochondrial Protein Humans UnknownInhibitorDetails Zonisamide Carbonic anhydrase 5B, mitochondrial Protein Humans UnknownInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 2 Ki (nM) 12.3 N/A N/A Details Ethoxzolamide Carbonic anhydrase 2 Ki (nM) 5.4 N/A N/A Details Topiramate Carbonic anhydrase 2 Ki (nM) 10.3 N/A N/A Details Zonisamide Carbonic anhydrase 2 Ki (nM) 35.2 N/A N/A Details Zonisamide Carbonic anhydrase 2 Ki (nM) 10.3 N/A N/A Details