Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry

J Enzyme Inhib Med Chem. 2020 Dec;35(1):306-310. doi: 10.1080/14756366.2019.1698562.

Abstract

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (bCA) delivered >100 hits that either caused, on their own, a significant thermal shift (ΔTm, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of hCA II, IX and XII which were efficacious in vivo. Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.

Keywords: Differential scanning fluorimetry; carbonic anhydrase II; fragment-based drug discovery; primary sulphonamide; protein affinity; thermal shift assay; zinc binding group.

MeSH terms

  • Benzenesulfonamides
  • Carbonic Anhydrase II / antagonists & inhibitors*
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX / antagonists & inhibitors*
  • Carbonic Anhydrase IX / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Drug Evaluation, Preclinical
  • Fluorometry*
  • Humans
  • Molecular Structure
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • Carbonic Anhydrase II
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII

Grants and funding

This research was supported by the Russian Federation Government Megagrant 14.W03.031.0025.