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Through the use of crystallographic analysis, we investigate the structures of hCA IX\u2010saccharin 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\u2010specific interactions are identified, offering promising strategies for the development of isoform\u2010selective inhibitors that specifically target tumor\u2010associated 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.<\/jats:p>","DOI":"10.1002\/cmdc.202300454","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T03:25:37Z","timestamp":1697253937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-8147","authenticated-orcid":false,"given":"Janis","family":"Leitans","sequence":"first","affiliation":[{"name":"Latvian Biomedical Research and Study Center  Ratsupites 1 1067 Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4964-0984","authenticated-orcid":false,"given":"Andris","family":"Kazaks","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Center  Ratsupites 1 1067 Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janis","family":"Bogans","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Center  Ratsupites 1 1067 Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department Sezione di Scienze Farmaceutiche University of Florence  Via Ugo Schiff 6 50019 Sesto Fiorentino Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inara","family":"Akopjana","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Center  Ratsupites 1 1067 Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8845-0193","authenticated-orcid":false,"given":"Jekaterina","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Aizkraukles 21 1006 Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-1342","authenticated-orcid":false,"given":"Raivis","family":"Zalubovskis","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Aizkraukles 21 1006 Riga Latvia"},{"name":"Institute of Technology of Organic Chemistry Faculty of Materials Science and Applied Chemistry Riga Technical University  P. 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