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Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration
- Source :
- Biomolecules, Volume 10, Issue 2, Biomolecules, Vol 10, Iss 2, p 196 (2020)
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N&ndash<br />H and O&ndash<br />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.
- Subjects :
- lcsh:QR1-502
Normal Distribution
Ligands
DFT calculations
01 natural sciences
Biochemistry
lcsh:Microbiology
Histamine receptor
Histamine H2 receptor
Physics::Chemical Physics
Hardware_REGISTER-TRANSFER-LEVELIMPLEMENTATION
Density Functional Theory
deuteration
Quantitative Biology::Biomolecules
0303 health sciences
heavy drugs
receptor activation
Hydrogen bond
Chemistry
Methylhistamines
Famotidine
Quantitative Biology::Genomics
3. Good health
Solvent
Density functional theory
Protons
Cimetidine
Protein Binding
medicine.drug
Stereochemistry
computational chemistry
histamine receptor
hydrogen bonding
010402 general chemistry
Article
03 medical and health sciences
Physics::Atomic and Molecular Clusters
medicine
Humans
Molecule
Receptors, Histamine H2
Molecular Biology
030304 developmental biology
Binding Sites
Water
Deuterium
0104 chemical sciences
Drug Design
Subjects
Details
- ISSN :
- 2218273X
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Biomolecules
- Accession number :
- edsair.doi.dedup.....8da64484b262056676d277131c3863df