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Issue 3, 2011
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The importance of solvation in the design of ligands targeting membrane proteins

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Abstract

A crucial contribution to the ligand-receptor binding affinity is, in addition to their electrostatic and van der Waals interactions, the desolvation of the ligand. This is of special relevance in membrane proteins because the ligand has to be transferred from the aqueous environment to the transmembrane binding site crevice. Herein we report the synthesis of new serotonin 5-HT4receptor antagonists that replace a key carbonyl group by the thiocarbonyl bioisoster. This modification enhances experimental 5-HT4 receptor binding affinities by as much as 91 times. Free energy perturbation calculations have shown that the significant decrease of the penalty of desolvation, facilitating the entrance of the ligands into the binding site crevice, compensates for the weaker ligand-receptor interaction.

Graphical abstract: The importance of solvation in the design of ligands targeting membrane proteins

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Publication details

The article was received on 13 Dec 2010, accepted on 15 Dec 2010 and first published on 07 Feb 2011


Article type: Concise Article
DOI: 10.1039/C0MD00258E
Citation: Med. Chem. Commun., 2011,2, 160-164
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    The importance of solvation in the design of ligands targeting membrane proteins

    A. González, M. Murcia, B. Benhamú, M. Campillo, M. L. López-Rodríguez and L. Pardo, Med. Chem. Commun., 2011, 2, 160
    DOI: 10.1039/C0MD00258E

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