7M26
Human carbonic anhydrase II in complex with pioglitazone
Summary for 7M26
| Entry DOI | 10.2210/pdb7m26/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione, ... (4 entities in total) |
| Functional Keywords | glitazone drug class, lyase-lyase inhibitor complex, lyase/lyase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29492.63 |
| Authors | Mueller, S.L.,Peat, T.S. (deposition date: 2021-03-16, release date: 2022-02-02, Last modification date: 2023-10-18) |
| Primary citation | Mueller, S.L.,Chrysanthopoulos, P.K.,Halili, M.A.,Hepburn, C.,Nebl, T.,Supuran, C.T.,Nocentini, A.,Peat, T.S.,Poulsen, S.A. The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors-A Spin-Off Discovery from Fragment Screening. Molecules, 26:-, 2021 Cited by PubMed Abstract: The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SONH) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone , rosiglitazone and pioglitazone ) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen-deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs. PubMed: 34070212DOI: 10.3390/molecules26103010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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