Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII
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
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.
IdentifiersURN: urn:nbn:se:uu:diva-282368DOI: 10.1021/acs.jmedchem.5b01723ISI: 000372043400030PubMedID: 26805033OAI: oai:DiVA.org:uu-282368DiVA: diva2:916944
FunderSwedish Research Council, D0571301