Monday, August 19, 2013

The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand

Matthew R. Lockett, Heiko Lange, Benjamin Breiten, Annie Heroux, Woody Sherman, Dmitrij Rappoport, Patricia O. Yau, Philip W. Snyder, and George M. Whitesides Angew. Chem. Int. Ed. 2013, 52, 7714
Contributed by +Jan Jensen

Accurate modeling the hydrophobic effect (or effects) is probably the biggest challenge to computational drug design (see for example this CC Highlight).  The hydrophobic effect on protein-ligand binding is generally thought to come from the release of structured and entropically unfavorable water molecules from the hydrophobic surfaces of the ligand and binding pocket. However, is also possible that the release of strongly bound water molecules to the protein/or ligand contributes to this effect.

I find this article important for two reasons:

1) The thorough characterization, including x-ray structures, of the binding of homologous ligands provides a valuable benchmark for computational studies.  The authors show that fluorination, commonly thought to increase the hydrophobic contribution to the binding free energy indeed increases the entropy of binding, but does so without decreasing the binding free energy.

The fluorinated ligand is indeed more hydrophobic as measured by buffer/octanol partitioning so what's going on?  One answer may be the difference in strongly bound water molecules observed in the protein-ligand x-ray structures: six and ten for the un- and fluorinated ligand, respectively. However, a simple correction based on the number of strongly bound water molecules is unlikely: a homologous un- and fluorinated ligand pair showed large differences in the binding enthalpy and entropy but smaller difference in number of strongly bound water molecules (four and seven, respectibely).

2) The supplementary material provides a fantastic list of important papers in this area.  I have reproduced the list below and added links, where available, to the articles.

From supplementary materials
Water-centric view of protein-ligand binding (relevant references in chronological order).
4. Thermodynamic Solvent Isotope Effects and Molecular Hydrophobicity, Adv. Biophys. Chem. 1997, 6, 1 (not available on-line)

Enthalpy-entropy compensation in protein-ligand binding (relevant references in chronological order).

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