Volume 18, Issue 22 e202300454
Research Article

Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX

Dr. Janis Leitans

Corresponding Author

Dr. Janis Leitans

Latvian Biomedical Research and Study Center, Ratsupites 1, 1067 Riga, Latvia

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Dr. Andris Kazaks

Dr. Andris Kazaks

Latvian Biomedical Research and Study Center, Ratsupites 1, 1067 Riga, Latvia

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Janis Bogans

Janis Bogans

Latvian Biomedical Research and Study Center, Ratsupites 1, 1067 Riga, Latvia

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Prof. Claudiu T. Supuran

Prof. Claudiu T. Supuran

NEUROFARBA Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy

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Inara Akopjana

Inara Akopjana

Latvian Biomedical Research and Study Center, Ratsupites 1, 1067 Riga, Latvia

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Dr. Jekaterina Ivanova

Dr. Jekaterina Ivanova

Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia

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Dr. Raivis Zalubovskis

Dr. Raivis Zalubovskis

Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia

Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena iela 3, 1048 Riga, Latvia

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Dr. Kaspars Tars

Dr. Kaspars Tars

Latvian Biomedical Research and Study Center, Ratsupites 1, 1067 Riga, Latvia

Faculty of Biology, University of Latvia, Jelgavas 1, Riga, 1004 Riga, Latvia

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First published: 14 October 2023

Graphical Abstract

This study investigates the binding mechanisms of saccharin derivatives with human carbonic anhydrase IX (hCA IX), a vital antitumor target. Through crystallographic analysis, distinct binding modes were uncovered, revealing ligand-protein interactions pivotal for inhibitor efficacy and selectivity. This work enhances our understanding of hCA inhibitor binding and informs the rational design of potent agents.

Abstract

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.

Conflict of interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.