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

Biomolecules

Robert Vianello¹  Jan Keuschler²  Mojca Kržan²  Janez Mavri³ 

[1] Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR–10000 Zagreb, Croatia;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;

关键词: computational chemistry;    dft calculations;    deuteration;    heavy drugs;    histamine receptor;    receptor activation;    hydrogen bonding;   

DOI  :  10.3390/biom10020196

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown