RRC ID 54785
Author Hishinuma S, Tamura Y, Kobayashi C, Akatsu C, Shoji M.
Title Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H₁ Receptors.
Journal Int J Mol Sci
Abstract Cetirizine is a zwitterionic second-generation antihistamine containing R- and S-enantiomers, levocetirizine, and (S)-cetirizine. Levocetirizine is known to have a higher affinity for the histamine H₁ receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance of the formation of a salt bridge (electrostatic interaction) between the carboxylic group of levocetirizine and the Lys191 residue at the fifth transmembrane domain of human histamine H₁ receptors. In this study, we evaluated the roles of Lys191 in the regulation of the thermodynamic binding forces of levocetirizine in comparison with (S)-cetirizine. The binding enthalpy and entropy of these compounds were estimated from the van 't Hoff equation, by using the dissociation constants obtained from their displacement curves against the binding of [³H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H₁ receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H₁ receptors for levocetirizine than (S)-cetirizine was achieved by stronger forces of entropy-dependent hydrophobic binding of levocetirizine. The mutation of Lys191 to alanine reduced the affinities for levocetirizine and (S)-cetirizine, through a reduction in the entropy-dependent hydrophobic binding forces of levocetirizine and the enthalpy-dependent electrostatic binding forces of (S)-cetirizine. These results suggested that Lys191 differentially regulates the binding enthalpy and entropy of these enantiomers, and that Lys191 negatively regulates the enthalpy-dependent electrostatic binding forces of levocetirizine, contrary to the predictions derived from the ligand-receptor docking simulations.
Volume 19(12)
Published 2018-12-15
DOI 10.3390/ijms19124067
PII ijms19124067
PMID 30558340
PMC PMC6321019
MeSH Animals CHO Cells Cetirizine / pharmacology* Cricetulus Entropy Histamine H1 Antagonists, Non-Sedating / pharmacology* Humans Lysine / metabolism Protein Binding Receptors, Histamine H1 / metabolism* Thermodynamics
IF 4.183
Times Cited 0
Human and Animal Cells CHO-K1(RCB0285)