Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX.
X-ray crystallography
cancer
carbonic anhydrase IX
drug design
isoform selectivity
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
16 Nov 2023
16 Nov 2023
Historique:
revised:
12
10
2023
received:
21
08
2023
medline:
29
11
2023
pubmed:
14
10
2023
entrez:
14
10
2023
Statut:
ppublish
Résumé
This study explores the binding mechanisms of saccharin derivatives with human carbonic anhydrase IX (hCA IX), an antitumor drug target, with the aim of facilitating the design of potent and selective inhibitors. Through the use of crystallographic analysis, we investigate the structures of hCA IX-saccharin derivative complexes, unveiling their unique binding modes that exhibit both similarities to sulfonamides and distinct orientations of the ligand tail. Our comprehensive structural insights provide information regarding the crucial interactions between the ligands and the protein, shedding light on interactions that dictate inhibitor binding and selectivity. Through a comparative analysis of the binding modes observed in hCA II and hCA IX, isoform-specific interactions are identified, offering promising strategies for the development of isoform-selective inhibitors that specifically target tumor-associated hCA IX. The findings of this study significantly deepen our understanding of the binding mechanisms of hCA inhibitors, laying a solid foundation for the rational design of more effective inhibitors.
Identifiants
pubmed: 37837260
doi: 10.1002/cmdc.202300454
doi:
Substances chimiques
Carbonic Anhydrase IX
EC 4.2.1.1
Saccharin
FST467XS7D
Carbonic Anhydrases
EC 4.2.1.1
Antigens, Neoplasm
0
Protein Isoforms
0
Carbonic Anhydrase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300454Subventions
Organisme : European Regional Development Fund
ID : 1.1.1.2/VIAA/3/19/464
Organisme : European Regional Development Fund
ID : 1.1.1.2/VIAA/3/19/576
Informations de copyright
© 2023 Wiley-VCH GmbH.
Références
J. W. Deitmer, S. M. Theparambil, I. Ruminot, H. M. Becker, Front. Neurol. Neurosci. 2015, 8, 430.
M. A. Pinard, B. Mahon, R. McKenna, BioMed Res. Int. 2015, 2015, 453543.
C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2012, 27, 759-772.
S. K. Chia, C. C. Wykoff, P. H. Watson, C. Han, R. D. Leek, J. Pastorek, K. C. Gatter, P. Ratcliffe, A. L. Harris, J. Clin. Oncol. 2001, 19, 3660-3668.
M. Leppilampi, T. J. Karttunen, J. Kivela, M. O. Gut, S. Pastorekova, J. Pastorek, S. Parkkila, Transgenic Res. 2005, 14, 655-663.
P. Pan, M. Leppilampi, S. Pastorekova, J. Pastorek, A. Waheed, W. S. Sly, S. Parkkila, J. Physiol. 2006, 571, 319-327.
S. Chakravarty, K. K. Kannan, J. Mol. Biol. 1994, 243, 298-309.
Scozzafava, L. Menabuoni, F. Mincione, F. Briganti, G. Mincione, C. T. Supuran, J. Med. Chem. 1999, 42, 2641-2650.
K. Köhler, A. Hillebrecht, J. Schulze Wischeler, A. Innocenti, A. Heine, C. T. Supuran, G. Klebe, Angew. Chem. Int. Ed. Engl. 2007, 46, 7697-9.
J. Ivanova, J. Leitans, M. Tanc, A. Kazaks, R. Zalubovskis, C. T. Supuran, K. Tars, Chem. Commun. (Camb.) 2015, 51, 7108-7111.
V. Alterio, M. Tanc, J. Ivanova, R. Zalubovskis, I. Vozny, S. M. Monti, A. Di Fiore, G. De Simone, C. T. Supuran, Org. Biomol. Chem. 2015, 13, 4064-4069.
J. Ivanova, F. Carta, D. Vullo, J. Leitans, A. Kazaks, K. Tars, R. Žalubovskis, C. T. Supuran, Bioorg. Med. Chem. 2017, 25, 3583-3589.
P. Guglielmi, G. Rotondi, D. Secci, A. Angeli, P. Chimenti, A. Nocentini, A. Bonardi, P. Gratteri, S. Carradori, C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2020, 35, 1891-1905.
S. Bua, C. Lomelino, A. B. Murray, S. M. Osman, Z. A. ALOthman, M. Bozdag, H. A. Abdel-Aziz, W. M. Eldehna, R. McKenna, A. Nocentini, C. T. Supuran, J. Med. Chem. 2020, 63, 321-333.
J. Leitans, A. Kazaks, A. Balode, J. Ivanova, R. Zalubovskis, C. T. Supuran, K. Tars, J. Med. Chem. 2015, 58, 9004-9009.
G. De Simone, V. Alterio, C. T. Supuran, Expert Opin. Drug Discovery 2013, 8, 793-810.
J. Ivanova, B. Balode, R. Zalubovskis, J. Leitans, A. Kazaks, D. Vullo, K. Tars, C. T. Supuran, Bioorg. Med. Chem. 2017, 25, 857-863.
V. Alterio, M. Hilvo, A. Di Fiore, C. T. Supuran, P. Pan, S. Parkkila, A. Scaloni, J. Pastorek, S. Pastorekova, C. Pedone, A. Scozzafava, S. M. Monti, G. De Simone, Proc. Natl. Acad. Sci. USA 2009, 106, 16233-16238.
T. G. G. Battye, L. Kontogiannis, O. Johnson, H. R. Powell, A. G. W. Leslie, Acta Crystallogr. D Struct. Biol. 2007, 67, 271-281.
P. Evans, Acta Crystallogr D Struct Biol. 2006, 62, 72-82.
Vagin, A. Teplyakov, Acta Crystallogr D Struct Biol. 2010, 66, 22-5.
G. N. Murshudov, P. Skubák, A. A. Lebedev, N. S. Pannu, R. A. Steiner, R. A. Nicholls, M. D. Winn, F. Long, A. A. Vagin, Acta Crystallogr D Struct Biol. 2011, 67, 355-367.
P. Emsley, K. Cowtan, Acta Crystallogr D Struct Biol. 2004, 60, 2126-2132.
A. A. Lebedev, P. Young, M. N. Isupov, O. V. Moroz, A. A. Vagin, G. N. Murshudov, Acta Crystallogr D Struct Biol. 2012, 68, 431-440.