20.500.12556/RUL-133064 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 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. histamine receptor receptor activation hydrogen bonding computational chemistry DFT calculations deuteration heavy drugs histaminski receptor aktivacija receptorjev vodikove vezi kromatografija true false true Angleški jezik Slovenski jezik Članek v reviji 2021-11-10 10:48:33 2021-11-10 10:48:38 2022-09-12 04:14:41 0000-00-00 00:00:00 2020 0 0 10 str. iss. 2, art. 196 Vol. 10 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615 2218-273X 10.3390/biom10020196 34671833 RAZ_Krzan_Mojca_2020.pdf RAZ_Krzan_Mojca_2020.pdf 1 548A7DC51C16BBF8EB92459377D283D3 78e9103207aa260df8741a2a6ff9f56cfd871fa1ae0337806623fdd366660971 9fdd4d13-420b-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=150838 https://www.mdpi.com/2218-273X/10/2/196 1 5293c29c-420b-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=150837 Medicinska fakulteta 0 0 0