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Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration.
Biomolecules. 2020 Jan 29; 10(2)B

Abstract

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.

Authors+Show Affiliations

Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI-1104 Ljubljana, Slovenia.Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI-1104 Ljubljana, Slovenia.Laboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32013143

Citation

Kržan, Mojca, et al. "Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: a Lesson From Deuteration." Biomolecules, vol. 10, no. 2, 2020.
Kržan M, Keuschler J, Mavri J, et al. Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration. Biomolecules. 2020;10(2).
Kržan, M., Keuschler, J., Mavri, J., & Vianello, R. (2020). Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration. Biomolecules, 10(2). https://doi.org/10.3390/biom10020196
Kržan M, et al. Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: a Lesson From Deuteration. Biomolecules. 2020 Jan 29;10(2) PubMed PMID: 32013143.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration. AU - Kržan,Mojca, AU - Keuschler,Jan, AU - Mavri,Janez, AU - Vianello,Robert, Y1 - 2020/01/29/ PY - 2019/11/13/received PY - 2019/12/27/revised PY - 2020/01/24/accepted PY - 2020/2/5/entrez PY - 2020/2/6/pubmed PY - 2020/2/6/medline KW - DFT calculations KW - computational chemistry KW - deuteration KW - heavy drugs KW - histamine receptor KW - hydrogen bonding KW - receptor activation JF - Biomolecules JO - Biomolecules VL - 10 IS - 2 N2 - 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. SN - 2218-273X UR - https://www.unboundmedicine.com/medline/citation/32013143/Relevance_of_Hydrogen_Bonds_for_the_Histamine_H2_Receptor-Ligand_Interactions:_A_Lesson_from_Deuteration L2 - https://www.mdpi.com/resolver?pii=biom10020196 DB - PRIME DP - Unbound Medicine ER -
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