title: Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies.
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 ligand's hydrophobicity, pointing to the existence of a prebinding stage largely stabilized by a favorable packing of the ligand's 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.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gaspari
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Rechlin
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Rocchia
authors.affiliation: Small Molecule Platform/MIB, Merck KGaA, Merck Serono Research , Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwarz
authors.affiliation: Small Molecule Platform/MIB, Merck KGaA, Merck Serono Research , Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bomke
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Gerber
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna , 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D024402:Carbonic Anhydrase II / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D015394:Molecular Structure; D011485:Protein Binding; D013449:Sulfonamides / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
chemical_list: D013449:Sulfonamides; D024402:Carbonic Anhydrase II; D015032:Zinc