Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2023-10-14 DOI:10.1002/cmdc.202300454
Dr. Janis Leitans, Dr. Andris Kazaks, Janis Bogans, Prof. Claudiu T. Supuran, Inara Akopjana, Dr. Jekaterina Ivanova, Dr. Raivis Zalubovskis, Dr. Kaspars Tars
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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.

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糖精衍生物抑制碳酸酐酶IX的结构基础。
这项科学研究探索了糖精衍生物与抗肿瘤药物靶点人碳酸酐酶IX(hCA IX)的结合机制,目的是促进强效和选择性抑制剂的设计。通过使用晶体学分析,我们研究了hCA IX-糖精衍生物复合物的结构,揭示了它们独特的结合模式,既表现出与磺酰胺的相似性,又表现出配体尾部的不同取向。我们全面的结构见解提供了有关配体和蛋白质之间关键相互作用的信息,揭示了决定抑制剂结合和选择性的相互作用。通过对在hCA II和hCA IX中观察到的结合模式的比较分析,确定了同种型特异性相互作用,为开发特异性靶向肿瘤相关hCA IX的同种型选择性抑制剂提供了有希望的策略。本研究的发现显著加深了我们对hCA抑制剂结合机制的理解,为合理设计更有效的抑制剂奠定了坚实的基础。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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