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Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors
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 H(1) receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321019/ https://www.ncbi.nlm.nih.gov/pubmed/30558340 http://dx.doi.org/10.3390/ijms19124067 |
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author | Hishinuma, Shigeru Tamura, Yuri Kobayashi, Chihiro Akatsu, Chizuru Shoji, Masaru |
author_facet | Hishinuma, Shigeru Tamura, Yuri Kobayashi, Chihiro Akatsu, Chizuru Shoji, Masaru |
author_sort | Hishinuma, Shigeru |
collection | PubMed |
description | 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 H(1) 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 H(1) 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 [(3)H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H(1) receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H(1) 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. |
format | Online Article Text |
id | pubmed-6321019 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-63210192019-01-07 Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors Hishinuma, Shigeru Tamura, Yuri Kobayashi, Chihiro Akatsu, Chizuru Shoji, Masaru Int J Mol Sci Communication 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 H(1) 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 H(1) 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 [(3)H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H(1) receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H(1) 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. MDPI 2018-12-15 /pmc/articles/PMC6321019/ /pubmed/30558340 http://dx.doi.org/10.3390/ijms19124067 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Hishinuma, Shigeru Tamura, Yuri Kobayashi, Chihiro Akatsu, Chizuru Shoji, Masaru Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title_full | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title_fullStr | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title_full_unstemmed | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title_short | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H(1) Receptors |
title_sort | differential regulation of thermodynamic binding forces of levocetirizine and (s)-cetirizine by lys191 in human histamine h(1) receptors |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321019/ https://www.ncbi.nlm.nih.gov/pubmed/30558340 http://dx.doi.org/10.3390/ijms19124067 |
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