Relevance of hydrogen bonds for the histamine H2 receptor-ligand interactions

ǂa ǂlesson from deuteration

Mojca Kržan (Author), Jan Keuschler (Author), Janez Mavri (Author), Robert Vianello (Author)

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.

Keywords

histaminski receptor;aktivacija receptorjev;vodikove vezi;kromatografija;histamine receptor;receptor activation;hydrogen bonds;

Data

Language:	English
Year of publishing:	2020
Typology:	1.01 - Original Scientific Article
Organization:	KI - National Institute of Chemistry
UDC:	615
COBISS:	34671833
ISSN:	2218-273X
Views:	178
Downloads:	66
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	Slovenian
Secondary keywords:	histaminski receptor;aktivacija receptorjev;vodikove vezi;kromatografija;
Type (COBISS):	Article
Pages:	str. 1-10
Volume:	ǂVol. ǂ10
Issue:	ǂno. ǂ2
Chronology:	2020
DOI:	10.3390/biom10020196
ID:	13870645