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Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. (Danielson group)ORCID iD: 0000-0002-1135-2744
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, 2083-2093 p.Article in journal (Refereed) Published
Abstract [en]

To get a better understanding of the possibility of developing selective carbonic anhydrase (CA) inhibitors, interactions between 17 benzenesulphonamide ligands and 6 human CAs (full-length CA I, II, VII, and XIII and catalytic domains of CA IX and XII) were characterized using surface plasmon resonance and fluorescent-based thermal shift assays. Kinetics revealed that the strongest binders had subnanomolar affinities with low dissociation rates (i.e., kd values around 1 × 10(-3) s(-1)) or were essentially irreversible. Chemodynamic analysis of the interactions highlighted an intrinsic mechanism of the CA-sulphonamide interaction kinetics and showed that slow dissociation rates were mediated by large hydrophobic contacts. The studied inhibitors demonstrated a high cross-reactivity within the protein family. However, according to chemical phylogenetic analysis developed for kinetic data, several ligands were found to be selective against certain CA isozymes, indicating that it should be possible to develop selective CA inhibitors suitable for clinical use.

Place, publisher, year, edition, pages
2016. Vol. 59, no 5, 2083-2093 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-282368DOI: 10.1021/acs.jmedchem.5b01723ISI: 000372043400030PubMedID: 26805033OAI: oai:DiVA.org:uu-282368DiVA: diva2:916944
Funder
Swedish Research Council, D0571301
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-11-30Bibliographically approved

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Talibov, Vladimir ODanielson, Helena U.

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