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

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• 作者：Roberto Gaspari ; Chris Rechlin ; Andreas Heine ; Giovanni Bottegoni ; Walter Rocchia ; Daniel Schwarz ; Jörg Bomke ; Hans-Dieter Gerber ; Gerhard Klebe ; Andrea Cavalli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：59
• 期：9
• 页码：4245-4256
• 全文大小：619K
• 年卷期：0
• ISSN：1520-4804

文摘

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 (k_on) 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.