Relevance of hydrogen bonds for the histamine H2 receptor-ligand interactions : a lesson from deuteration

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

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.

• Jezik: Angleški jezik
• Ključne besede: histamine receptor, receptor activation, hydrogen bonding, computational chemistry, DFT calculations, deuteration, heavy drugs
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: 10 str.
• Številčenje: Vol. 10, iss. 2, art. 196
• PID: 20.500.12556/RUL-133064
• UDK: 615
• ISSN pri članku: 2218-273X
• DOI: 10.3390/biom10020196
• COBISS.SI-ID: 34671833
• Datum objave v RUL: 10.11.2021

Gradivo je del revije

• Naslov: Biomolecules
• Skrajšan naslov: Biomolecules
• Založnik: MDPI
• ISSN: 2218-273X
• COBISS.SI-ID: 519952921

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 01.02.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: histaminski receptor, aktivacija receptorjev, vodikove vezi, kromatografija