{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T15:07:08Z","timestamp":1761491228993,"version":"build-2065373602"},"reference-count":65,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["IC180100021"],"award-info":[{"award-number":["IC180100021"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry for Research and University","award":["2017XYBP2R"],"award-info":[{"award-number":["2017XYBP2R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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-SO2NH2) 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 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen\u2013deuterium 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.<\/jats:p>","DOI":"10.3390\/molecules26103010","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T23:34:46Z","timestamp":1621380886000},"page":"3010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors\u2014A Spin-Off Discovery from Fragment Screening"],"prefix":"10.3390","volume":"26","author":[{"given":"Sarah L.","family":"Mueller","sequence":"first","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia"},{"name":"ARC Centre for Fragment-Based Design, Griffith University, Nathan, Brisbane, QLD 4111, Australia"},{"name":"CSIRO, Biomedical Manufacturing Program, Parkville, Melbourne, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panagiotis K.","family":"Chrysanthopoulos","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria A.","family":"Halili","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia"},{"name":"ARC Centre for Fragment-Based Design, Griffith University, Nathan, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caryn","family":"Hepburn","sequence":"additional","affiliation":[{"name":"Waters Australia Pty Ltd., Rydalmere, NSW 2116, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Nebl","sequence":"additional","affiliation":[{"name":"CSIRO, Biomedical Manufacturing Program, Parkville, Melbourne, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Universit\u00e0 Degli Studi di Firenze, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Universit\u00e0 Degli Studi di Firenze, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-0831","authenticated-orcid":false,"given":"Thomas S.","family":"Peat","sequence":"additional","affiliation":[{"name":"CSIRO, Biomedical Manufacturing Program, Parkville, Melbourne, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4494-3687","authenticated-orcid":false,"given":"Sally-Ann","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia"},{"name":"ARC Centre for Fragment-Based Design, Griffith University, Nathan, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nrd.2016.109","article-title":"Twenty years on: The impact of fragments on drug discovery","volume":"15","author":"Erlanson","year":"2016","journal-title":"Nat. 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