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

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 196 ◽  
Author(s):  
Mojca Kržan ◽  
Jan Keuschler ◽  
Janez Mavri ◽  
Robert Vianello
Keyword(s):  
Hydrogen Bonding ◽  
Active Sites ◽  
Density Functional ◽  
Receptor Activation ◽  
Histamine H2 Receptor ◽  
Therapeutic Practice ◽  
H2 Receptor ◽  
Ligand Interactions ◽  
Solvent Molecules ◽  
Near Future

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.

scholarly journals The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6017
Author(s):  
Lucija Hok ◽  
Janez Mavri ◽  
Robert Vianello
Keyword(s):  
Hydrogen Bonding ◽  
Binding Energy ◽  
Binding Free Energy ◽  
Receptor Activation ◽  
Dynamics Simulation ◽  
Computational Techniques ◽  
Aqueous Environment ◽  
Total Binding Energy ◽  
H2 Receptor ◽  
Hydrogen Bonding Interactions

We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

scholarly journals Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory

2020 ◽  
Author(s):  
Kodakkat Parambil Safna Hussan ◽  
Indulekha Jayarajan Jithin Raj ◽  
Sailaja Urpayil ◽  
Mohamed Shahin Thayyil
Keyword(s):  
Density Functional Theory ◽  
Molecular Orbital ◽  
Density Functional ◽  
Receptor Antagonists ◽  
H2 Receptor Antagonists ◽  
Functional Theory ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
H2 Blockers ◽  
Many Body Systems

Density functional theory (DFT) is a quantum mechanical approach used to investigate the electronic structure (principally the ground state) of many-body systems, in particular atoms, molecules, and the condensed phases. In this work, we have used DFT/B3LYP/6-31+G(d) level of theory to get insight into the molecular geometry and thermochemical properties of histamine H2-receptor antagonists. Histamine H2-receptor antagonists or H2 blockers are a group of pharmaceutical ingredients that reduce the amount of acid produced by the cells in the lining of the stomach. The potential H2 blockers include cimetidine, famotidine, nizatidine, and ranitidine. The detailed theoretical investigation on the listed H2 blockers in terms of their thermochemical parameters and global descriptive parameters revealed that, though famotidine is the best among them with highest Gibbs free energy, nizatidine showed higher biological activity with high softness, low hardness, and high electrophilicity index. The theoretical vibrational spectra of these four Histamine H2-receptor antagonists were analyzed and the infrared spectra of nizatidine was compared with the experimental IR spectra, and found to be good agreement with the experimental values. Further, frontier molecular orbitals especially the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were determined and the activation energy of the selected samples were calculated. In addition to this, the amorphisation technique were employed to enhance the solubility and bio availability of the best biologically active H2 blocker nizatidine using broadband dielectric spectroscopy.

Electrostatic medium effects upon histamine H2 receptor activation

1991 ◽  
Vol 236 (1-2) ◽  
pp. 201-209 ◽  
Author(s):  
Juan S. Gómez-Jeria ◽  
Julia Parra-Mouchet ◽  
Demian Morales-Lagos
Keyword(s):  
Receptor Activation ◽  
Medium Effects ◽  
Histamine H2 Receptor ◽  
H2 Receptor
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