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Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration†
We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N–H and O–H bonds to assess the effect of deuteration on the binding of agonists (2-methylhistamine and 4-methylhistamine) and antagonists (cimetidine and famotidine) to the histamine H2...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072573/ https://www.ncbi.nlm.nih.gov/pubmed/32013143 http://dx.doi.org/10.3390/biom10020196 |
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author | Kržan, Mojca Keuschler, Jan Mavri, Janez Vianello, Robert |
author_facet | Kržan, Mojca Keuschler, Jan Mavri, Janez Vianello, Robert |
author_sort | Kržan, Mojca |
collection | PubMed |
description | We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N–H and O–H bonds to assess the effect of deuteration on the binding of agonists (2-methylhistamine and 4-methylhistamine) and antagonists (cimetidine and famotidine) to the histamine H2 receptor. The results show that deuteration significantly increases the affinity for 4-methylhistamine and reduces it for 2-methylhistamine, while leaving it unchanged for both antagonists, which is found in excellent agreement with experiments. The revealed trends are interpreted in the light of the altered strength of the hydrogen bonding upon deuteration, known as the Ubbelohde effect, which affects ligand interactions with both active sites residues and solvent molecules preceding the binding, thus providing strong evidence for the relevance of hydrogen bonding for this process. In addition, computations further underline an important role of the Tyr250 residue for the binding. The obtained insight is relevant for the therapy in the context of (per)deuterated drugs that are expected to enter therapeutic practice in the near future, while this approach may contribute towards understanding receptor activation and its discrimination between agonists and antagonists. |
format | Online Article Text |
id | pubmed-7072573 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70725732020-03-19 Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† Kržan, Mojca Keuschler, Jan Mavri, Janez Vianello, Robert Biomolecules Article We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N–H and O–H bonds to assess the effect of deuteration on the binding of agonists (2-methylhistamine and 4-methylhistamine) and antagonists (cimetidine and famotidine) to the histamine H2 receptor. The results show that deuteration significantly increases the affinity for 4-methylhistamine and reduces it for 2-methylhistamine, while leaving it unchanged for both antagonists, which is found in excellent agreement with experiments. The revealed trends are interpreted in the light of the altered strength of the hydrogen bonding upon deuteration, known as the Ubbelohde effect, which affects ligand interactions with both active sites residues and solvent molecules preceding the binding, thus providing strong evidence for the relevance of hydrogen bonding for this process. In addition, computations further underline an important role of the Tyr250 residue for the binding. The obtained insight is relevant for the therapy in the context of (per)deuterated drugs that are expected to enter therapeutic practice in the near future, while this approach may contribute towards understanding receptor activation and its discrimination between agonists and antagonists. MDPI 2020-01-29 /pmc/articles/PMC7072573/ /pubmed/32013143 http://dx.doi.org/10.3390/biom10020196 Text en © 2020 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 | Article Kržan, Mojca Keuschler, Jan Mavri, Janez Vianello, Robert Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title | Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title_full | Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title_fullStr | Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title_full_unstemmed | Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title_short | Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration† |
title_sort | relevance of hydrogen bonds for the histamine h2 receptor-ligand interactions: a lesson from deuteration† |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072573/ https://www.ncbi.nlm.nih.gov/pubmed/32013143 http://dx.doi.org/10.3390/biom10020196 |
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