Insights into the binding modes of CC chemokine receptor 4 (CCR4) inhibitors: a combined approach involving homology modelling, docking, and molecular dynamics simulation studies

2015 ◽  
Vol 11 (2) ◽  
pp. 618-634 ◽  
Author(s):  
Changdev G. Gadhe ◽  
Mi-hyun Kim
Keyword(s):  
Chemokine Receptor ◽  
Cell Lymphoma ◽  
Homology Modelling ◽  
Vital Role ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
Cc Chemokine ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

CC chemokine receptor 4 (CCR4), a G protein-coupled receptor (GPCR), plays a vital role in the progression of asthma, T-cell lymphoma, inflammation, and Alzheimer's disease.

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

CC Chemokine Receptor 4-Positive Diffuse Large B-Cell Lymphoma Involving the Skin: A Case Report

2005 ◽  
Vol 82 (2) ◽  
pp. 148-151 ◽  
Author(s):  
Takashi Ishida ◽  
Hiroshi Inagaki ◽  
Shigeru Kusumoto ◽  
Atsushi Inagaki ◽  
Hirokazu Komatsu ◽  
...  
Keyword(s):  
Case Report ◽  
B Cell ◽  
Chemokine Receptor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cc Chemokine ◽  
Large B Cell Lymphoma ◽  
Chemokine Receptor 4 ◽  
Large B Cell

Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients With Relapsed Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

2014 ◽  
Vol 32 (11) ◽  
pp. 1157-1163 ◽  
Author(s):  
Michinori Ogura ◽  
Takashi Ishida ◽  
Kiyohiko Hatake ◽  
Masafumi Taniwaki ◽  
Kiyoshi Ando ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Chemokine Receptor ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Cc Chemokine ◽  
Multicenter Phase ◽  
Chemokine Receptor 4

Purpose CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL). Patients and Methods Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Results A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations (± standard deviation) after the eighth infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable. Conclusion Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted.

scholarly journals Chemokine-like factor 1 is a functional ligand for CC chemokine receptor 4 (CCR4)

Life Sciences ◽  
2006 ◽  
Vol 78 (6) ◽  
pp. 614-621 ◽  
Author(s):  
Ying Wang ◽  
Yingmei Zhang ◽  
Xue Yang ◽  
Wenling Han ◽  
Yanan Liu ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Cc Chemokine ◽  
Chemokine Receptor 4

Suppressive effects of a novel CC chemokine receptor 4 antagonist on Th2 cell trafficking in ligand- and antigen-induced mouse models

2013 ◽  
Vol 720 (1-3) ◽  
pp. 335-343 ◽  
Author(s):  
Takaki Komiya ◽  
Tetsuya Sugiyama ◽  
Kazuhiko Takeda ◽  
Noriki Watanabe ◽  
Masamichi Imai ◽  
...  
Keyword(s):  
Mouse Models ◽  
Chemokine Receptor ◽  
Cell Trafficking ◽  
Cc Chemokine ◽  
Th2 Cell ◽  
Chemokine Receptor 4

CC chemokine receptor 4

1997 ◽  
pp. 165-166
Author(s):  
Krishna Vaddi ◽  
Margaret Keller ◽  
Robert C. Newton
Keyword(s):  
Chemokine Receptor ◽  
Cc Chemokine ◽  
Chemokine Receptor 4
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