Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies

Research output: Contribution to journalArticlepeer-review


  • Roberto Gaspari
  • Chris Rechlin
  • Andreas Heine
  • Walter Rocchia
  • Daniel Schwarz
  • Jörg Bomke
  • Hans Dieter Gerber
  • Gerhard Klebe
  • Andrea Cavalli

Colleges, School and Institutes

External organisations

  • Istituto Italiano di Tecnologia
  • Philipps-Universitat Marburg
  • Merck Serono S.A
  • Università di Bologna


The binding of sulfonamides to human carbonic anhydrase II (hCAII) is a complex and long-debated example of protein-ligand recognition and interaction. In this study, we investigate the para-substituted n-alkyl and hydroxyethylene-benzenesulfonamides, providing a complete reconstruction of their binding pathway to hCAII by means of large-scale molecular dynamics simulations, density functional calculations, surface plasmon resonance (SPR) measurements, and X-ray crystallography experiments. Our analysis shows that the protein-ligand association rate (kon) dramatically increases with the ligands hydrophobicity, pointing to the existence of a prebinding stage largely stabilized by a favorable packing of the ligands apolar moieties with the hCAII "hydrophobic wall". The characterization of the binding pathway allows an unprecedented understanding of the structure-kinetic relationship in hCAII/benzenesulfonamide complexes, depicting a paradigmatic scenario for the multistep binding process in protein-ligand systems.


Original languageEnglish
Pages (from-to)4245-4256
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number9
Early online date23 Dec 2015
Publication statusPublished - 12 May 2016

ASJC Scopus subject areas