7M26

Human carbonic anhydrase II in complex with pioglitazone

7M26 の概要

• エントリーDOI: 10.2210/pdb7m26/pdb
• 分子名称: 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)
• 機能のキーワード: glitazone drug class, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29492.63

構造登録者

Mueller, S.L.,Peat, T.S. (登録日: 2021-03-16, 公開日: 2022-02-02, 最終更新日: 2023-10-18)

主引用文献

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

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: 34070212
DOI: 10.3390/molecules26103010

実験手法

X-RAY DIFFRACTION (1.3 Å)