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

Roberto Gaspari, Chris Rechlin, Andreas Heine, Giovanni Bottegoni, Walter Rocchia, Daniel Schwarz, Jörg Bomke, Hans Dieter Gerber, Gerhard Klebe*, Andrea Cavalli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

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
Volume59
Issue number9
Early online date23 Dec 2015
DOIs
Publication statusPublished - 12 May 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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