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

Talibov VO, Linkuvienė V, Matulis D, Danielson UH

J. Med. Chem. 59 (5) 2083-2093 [2016-03-10; online 2016-01-26]

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.

Drug Discovery and Development (DDD) [Collaborative]

QC bibliography QC xrefs

PubMed 26805033

DOI 10.1021/acs.jmedchem.5b01723

Crossref 10.1021/acs.jmedchem.5b01723

Biophysical Screening and Characterization