Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2202360. doi: 10.1080/14756366.2023.2202360.

Abstract

Considering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active site among the other hCA isoforms, i.e. the Leu198/Phe198 substitution which interferes with the binding of aromatic/heterocyclic sulfonamides and other inhibitors. Thus, new aliphatic primary sulfonamides possessing long and flexible (CH2)nSO2NH2 moieties were designed to coordinate the zinc(II) ion, bypassing the bulky Phe198 residue. They incorporate 1,2,3-triazole linkers which connect the tail moieties to the sulfonamide head, enhancing thus the contacts at the active site entrance. Some of these compounds act as nanomolar and selective inhibitors of hCA III over other isoforms. Docking/molecular dynamics simulations were used to investigate ligand/target interactions for these sulfonamides which might improve our understanding of the physio-pathological roles of hCA III.

Keywords: Drug design; click chemistry; hCA III; inhibition; metalloenzyme; molecular dynamics.

MeSH terms

  • Carbonic Anhydrase Inhibitors* / chemistry
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Sulfonamides* / chemistry

Substances

  • Carbonic Anhydrase Inhibitors
  • Sulfonamides

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.