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Molecules
Volume 26
Issue 10
10.3390/molecules26103010
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Article

The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening

by
Sarah L. Mueller
1,2,3,
Panagiotis K. Chrysanthopoulos
1,
Maria A. Halili
1,2,
Caryn Hepburn
4,
Tom Nebl
3,
Claudiu T. Supuran
5,
Alessio Nocentini
5,
Thomas S. Peat
3 and
Sally-Ann Poulsen
1,2,*
1
Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia
2
ARC Centre for Fragment-Based Design, Griffith University, Nathan, Brisbane, QLD 4111, Australia
3
CSIRO, Biomedical Manufacturing Program, Parkville, Melbourne, VIC 3052, Australia
4
Waters Australia Pty Ltd., Rydalmere, NSW 2116, Australia
5
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Università Degli Studi di Firenze, Sesto Fiorentino, 50019 Florence, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Mercedes Alfonso-Prieto
Molecules 2021, 26(10), 3010; https://doi.org/10.3390/molecules26103010
Received: 15 April 2021 / Revised: 11 May 2021 / Accepted: 14 May 2021 / Published: 18 May 2021
(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)
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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-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–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. View Full-Text
Keywords: diabetes; carbonic anhydrase; metalloenzyme; glitazones; fragment-based drug discovery; zinc binding group; native mass spectrometry; protein crystallography diabetes; carbonic anhydrase; metalloenzyme; glitazones; fragment-based drug discovery; zinc binding group; native mass spectrometry; protein crystallography
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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 2021, 26, 3010. https://doi.org/10.3390/molecules26103010

AMA Style

Mueller SL, Chrysanthopoulos PK, Halili MA, Hepburn C, Nebl T, Supuran CT, Nocentini A, Peat TS, Poulsen S-A. The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening. Molecules. 2021; 26(10):3010. https://doi.org/10.3390/molecules26103010

Chicago/Turabian Style

Mueller, Sarah L., Panagiotis K. Chrysanthopoulos, Maria A. Halili, Caryn Hepburn, Tom Nebl, Claudiu T. Supuran, Alessio Nocentini, Thomas S. Peat, and Sally-Ann Poulsen. 2021. "The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening" Molecules 26, no. 10: 3010. https://doi.org/10.3390/molecules26103010

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