2H15
Carbonic anhydrase inhibitors: Clashing with Ala65 as a means of designing isozyme-selective inhibitors that show low affinity for the ubiquitous isozyme II
Summary for 2H15
| Entry DOI | 10.2210/pdb2h15/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total) |
| Functional Keywords | carbonic anhydrase, inhibitors, lyase |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm : P00918 |
| Total number of polymer chains | 1 |
| Total formula weight | 29893.44 |
| Authors | Winum, J.Y.,Temperini, C.,Ciattini, S.,Scozzafava, A.,Supuran, C.T. (deposition date: 2006-05-16, release date: 2007-03-27, Last modification date: 2024-02-14) |
| Primary citation | Winum, J.Y.,Temperini, C.,El Cheikh, K.,Innocenti, A.,Vullo, D.,Ciattini, S.,Montero, J.L.,Scozzafava, A.,Supuran, C.T. 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. J.Med.Chem., 49:7024-7031, 2006 Cited by PubMed Abstract: 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. PubMed: 17125255DOI: 10.1021/jm060807n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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