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 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 Unraveling the contributions of hydrogen-bonding interactions to the activity of native and non-native ligands in the quorum-sensing receptor LasR

2015 ◽  
Vol 13 (5) ◽  
pp. 1453-1462 ◽  
Author(s):  
Joseph P. Gerdt ◽  
Christine E. McInnis ◽  
Trevor L. Schell ◽  
Helen E. Blackwell
Keyword(s):  
Hydrogen Bonding ◽  
Quorum Sensing ◽  
Receptor Activation ◽  
Synthetic Analogues ◽  
Hydrogen Bonding Interactions ◽  
Polar Interactions ◽  
Native Ligand

Systematic analyses of mutant LasR quorum-sensing receptors with its native ligand and a suite of synthetic analogues reveal the importance of specific polar interactions for native receptor activation.

Synergistic host–guest hydrophobic and hydrogen bonding interactions in the complexation between endo-functionalized molecular tube and strongly hydrophilic guest molecules in aqueous solution

2018 ◽  
Vol 20 (24) ◽  
pp. 16540-16550 ◽  
Author(s):  
Rabindranath Paul ◽  
Sandip Paul
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Hydrogen Bonding ◽  
Molecular Dynamics Simulation ◽  
Simulation Study ◽  
Dynamics Simulation ◽  
Guest Molecules ◽  
Hydrogen Bonding Interactions ◽  
Molecular Tube

Molecular dynamics simulation study of the recognition of hydrophilic molecules by an endo-functionalized molecular tube in aqueous solution.

scholarly journals Inhibitory Reactivity of Capsaicin with α-Amylase and α-Glucosidase Related to Antidiabetes using Molecular Docking and Quantum Calculation Methods

2018 ◽  
Vol 34 (5) ◽  
pp. 2211-2228 ◽  
Author(s):  
Kultida Thongnum ◽  
Saksit Chanthai
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Binding Energy ◽  
Inhibition Efficiency ◽  
Binding Free Energy ◽  
Total Binding Energy ◽  
Quantum Calculation ◽  
Total Binding ◽  
Alternative Drug ◽  
Diabetes Drug

This work aims to investigate the inhibitory activity of capsaicin, which is one of capsaicinoid compounds, on these enzymes using a molecular docking and quantum calculation. Acarbose, a commercial diabetes drug, was also investigated for comparison. The docking results revealed that acarbose yields better inhibition efficiency with binding free energy (ΔGbinding) of about -8.2 to -11.9 kcal/mol, and inhibition constant (Ki) of about 0.0002 to 0.4 µM, whereas capsaicin provided the ΔGbinding of -5.8 to -6.1 kcal/mol and Ki of 23.7 to 45.9 µM. The total binding energy (ΔEbinding) between each inhibitor and amino acids in active site of enzyme obtained from quantum calculation with MP2/6-31G(d,p) level is in agreement with the ΔGbinding, i.e. the ΔEbinding of acarbose was larger negative than that of capsaicin. The amino acids interacting with inhibitor as hydrogen bond mainly contribute to the total binding energy. Nevertheless, it could be concluded that capsaicinoids have high potential to be developed as an alternative drug for diabetes disease.

scholarly journals Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 674
Author(s):  
Ziyad Tariq Muhseen ◽  
Alaa R. Hameed ◽  
Halah M. H. Al-Hasani ◽  
Sajjad Ahmad ◽  
Guanglin Li
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Compounds ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Antiviral Compounds ◽  
Rational Drug ◽  
Key Residues

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

Effects of chain polarity of hindered phenol on the damping properties of polymer-based hybrid materials: insights into the molecular mechanism

2020 ◽  
Vol 40 (5) ◽  
pp. 394-402
Author(s):  
Qiaoman Hu ◽  
Junhui Wang ◽  
Kangming Xu ◽  
Hongdi Zhou ◽  
Yue Huang ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Mechanical Analysis ◽  
Dynamics Simulation ◽  
Damping Properties ◽  
Structure Variation ◽  
Hydrogen Bonding Interactions ◽  
Ft Ir ◽  
Hindered Phenol ◽  
Damping Materials ◽  
The Relationship

AbstractFor hindered phenol (HP)/polymer-based hybrid damping materials, the damping properties are greatly affected by the structure variation of HPs. However, the unclear relationship between them limits the exploitation of such promising materials. Therefore, three HPs with different chain polarity were synthesized to explore the relationship in this paper. The structures of the HPs were firstly confirmed by Nuclear Magnetic Resonance Spectrum, Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Diffraction (XRD). For further prepared HP/polyurethane hybrids, FT-IR and XRD were also adopted to confirm the hydrogen bonding interactions and micromorphologies. And, Molecular dynamics simulation was further used to characterize the effects of polarity variation on the hydrogen bonding interactions and chain packing of the hybrids in a quantitative manner. Then, combined with dynamic mechanical analysis, the relationship between the chain polarity variation of the hindered phenols and the damping properties was established.

scholarly journals Phytomedicine in Disease Management: In-Silico Analysis of the Binding Affinity of Artesunate and Azadirachtin for Malaria Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael P. Okoh ◽  
Rajeev K. Singla ◽  
Chijioke Madu ◽  
Opeyemi Soremekun ◽  
Johnson Adejoh ◽  
...  
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Root Mean Square ◽  
Structural Changes ◽  
Binding Free Energy ◽  
Traditional Healers ◽  
Scaffolding Protein ◽  
Binding Potential ◽  
Total Binding Energy ◽  
Mean Square

In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype.

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