VIRTUAL TARGET CONSTRUCTION FOR STRUCTURE-BASED SCREENING IN THE DISCOVERY OF HISTAMINE H2 RECEPTOR LIGANDS

Objective: This study aimed to develop validated targets to be employed in structure-based virtual screening (SBVS) to discover ligands for the human histamine H2 receptor (hHRH2). Methods: The virtual targets construction was initiated by homology modeling with the reference compound ranitidine as the ligand followed by 100 ns molecular dynamics (MD) simulations. During MD simulations, the snapshot with the lowest value of the free energy of binding was selected for further validation by re-docking simulations. All simulations were performed in YASARA-Structure. Results: The research presented here resulted in one validated target for the SBVS. Additionally, by employing a clustering module in MD simulations analysis in YASARA-Structure, more than ten different virtual targets are also available for further uses. Conclusion: The virtual targets resulted in this research offer possibilities to construct valid SBVS protocols to identify ligands for the hHRH2.

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Homology Modeling and Antagonist Binding Site Study of the Human Histamine H2 Receptor

Medicinal Chemistry ◽

10.2174/1573406411208061084 ◽

2012 ◽

Vol 8 (6) ◽

pp. 1084-1092 ◽

Cited By ~ 1

Author(s):

Jing Zhang ◽

Tao Qi ◽

Jing Wei

Keyword(s):

Homology Modeling ◽

Binding Site ◽

Histamine H2 Receptor ◽

H2 Receptor ◽

Antagonist Binding ◽

Human Histamine

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Author Correction: NanoBRET binding assay for histamine H2 receptor ligands using live recombinant HEK293T cells

Scientific Reports ◽

10.1038/s41598-021-91782-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lukas Grätz ◽

Katharina Tropmann ◽

Merlin Bresinsky ◽

Christoph Müller ◽

Günther Bernhardt ◽

...

Keyword(s):

Binding Assay ◽

Receptor Ligands ◽

Histamine H2 Receptor ◽

H2 Receptor

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

Molecules ◽

10.3390/molecules26113293 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3293

Author(s):

Mateusz Zalewski ◽

Sebastian Kmiecik ◽

Michał Koliński

Keyword(s):

Molecular Dynamics ◽

Geometry Optimization ◽

Computational Prediction ◽

Md Simulations ◽

Coarse Grained ◽

Ligand Interaction ◽

Vast Number ◽

Docking Simulations ◽

Peptide Models ◽

Peptide Complexes

One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.

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Structure-Activity Relationships of Histamine H2 Receptor Ligands+

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557043403242 ◽

2004 ◽

Vol 4 (9) ◽

pp. 941-954 ◽

Cited By ~ 25

Author(s):

Stefan Dove ◽

Sigurd Elz ◽

Roland Seifert ◽

Armin Buschauer

Keyword(s):

Receptor Ligands ◽

Histamine H2 Receptor ◽

H2 Receptor ◽

Structure Activity Relationships ◽

Structure Activity

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Docking-based screening of Ficus religiosa phytochemicals as inhibitors of human histamine H2 receptor

Pharmacognosy Magazine ◽

10.4103/pm.pm_49_17 ◽

2017 ◽

Vol 13 (51) ◽

pp. 706 ◽

Cited By ~ 2

Author(s):

Ashutosh Mani ◽

Amit Chaudhary ◽

BirendraSingh Yadav ◽

Swati Singh ◽

PramodKumar Maurya ◽

...

Keyword(s):

Ficus Religiosa ◽

Histamine H2 Receptor ◽

H2 Receptor ◽

Human Histamine

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Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

International Journal of Molecular Sciences ◽

10.3390/ijms21186693 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6693

Author(s):

Marcus Conrad ◽

Christian A. Söldner ◽

Yinglong Miao ◽

Heinrich Sticht

Keyword(s):

Molecular Dynamics ◽

G Protein ◽

Conformational Changes ◽

Structural Information ◽

Conformational Stability ◽

Site Directed Mutagenesis ◽

Active Conformation ◽

Histamine H2 Receptor ◽

H2 Receptor ◽

Ulcer Disease

The histamine H2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-Gs complex based on the structure of the ternary complex of the β2-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-Gs interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.

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