TY - JOUR
T1 - Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies
AU - Gaspari, Roberto
AU - Rechlin, Chris
AU - Heine, Andreas
AU - Bottegoni, Giovanni
AU - Rocchia, Walter
AU - Schwarz, Daniel
AU - Bomke, Jörg
AU - Gerber, Hans Dieter
AU - Klebe, Gerhard
AU - Cavalli, Andrea
PY - 2016/5/12
Y1 - 2016/5/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84969667426&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b01643
DO - 10.1021/acs.jmedchem.5b01643
M3 - Article
C2 - 26700575
AN - SCOPUS:84969667426
SN - 0022-2623
VL - 59
SP - 4245
EP - 4256
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -