Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII

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.