Paper Citing NAMD - Abstract
Gonzalez, Angel; Murcia, Marta; Benhamu, Bellinda; Campillo, Mercedes; Lopez-Rodriguez, Maria L.; Pardo, Leonardo
The importance of solvation in the design of ligands targeting membrane proteins
MEDCHEMCOMM, 2:160-164, MAR 2011
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-HT(4) receptor antagonists that replace a key carbonyl group by the thiocarbonyl bioisoster. This modification enhances experimental 5-HT(4) 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.
