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Open AccessArticle

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

1
Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI–1104 Ljubljana, Slovenia
2
Laboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI–1001 Ljubljana, Slovenia
3
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR–10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
This paper is dedicated to the memory of Prof. Dušan Hadži (1921–2019), a prominent researcher with a large impact on the hydrogen bond research, who recently passed away.
These authors contributed equally to this work.
Biomolecules 2020, 10(2), 196; https://doi.org/10.3390/biom10020196
Received: 13 November 2019 / Revised: 27 December 2019 / Accepted: 24 January 2020 / Published: 29 January 2020
(This article belongs to the Section Chemical Biology)
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. View Full-Text
Keywords: computational chemistry; DFT calculations; deuteration; heavy drugs; histamine receptor; receptor activation; hydrogen bonding computational chemistry; DFT calculations; deuteration; heavy drugs; histamine receptor; receptor activation; hydrogen bonding
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MDPI and ACS Style

Kržan, M.; Keuschler, J.; Mavri, J.; Vianello, R. Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration. Biomolecules 2020, 10, 196.

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