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Characterization of Adenosine Receptor in Its Native Environment: Insights From Molecular Dynamics Simulations of Palmitoylated/Glycosylated, Membrane-Integrated Human A2b Adenosine Receptor Publisher Pubmed



Mansourian M1 ; Madadkarsobhani A2, 3 ; Mahnam K4 ; Fassihi A1 ; Saghaie L1
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, School of Pharmacy, Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
  3. 3. Life Sciences Department, Barcelona Supercomputing Center (BSC), 08034 Barcelona, Spain
  4. 4. Biology Department, Faculty of Science, Shahrekord University, Shahrekord, Iran

Source: Journal of Molecular Modeling Published:2012


Abstract

Selective A2B receptor antagonists and agonists may play a role in important pathologies such as gastrointestinal, neurological (i.e., Alzheimer disease and dementia) and hypersensitive disorders (i.e., asthma), diabetes, atherosclerosis, restenosis and cancer. Hence, it is regarded as a good target for the development of clinically useful agents. In this study, the effects of lipid bilayer, N-acetylglucosamine and Spalmitoyl on the dynamic behavior of A2BAR model is explored. Homology modeling, molecular docking and molecular dynamics simulations were performed to explore structural features of A2BAR in the presence of lipid bilayer. Twenty ns MD simulation was performed on the constructed model inserted in a hydrated lipid bilayer to examine stability of the best model. OSIP339391 as the most potent antagonist was docked in the active site of the model. AnotherMD simulation was performed on the ligand-protein complex to explore effects of the bilayer on this complex. A similar procedure was performed for the modified protein with Nacetylglucosamine and S-palmitoyl moieties in its structure. Phe173 and Glu174 located in EL2 were determined to be involved in ligand-receptor interactions through p-p stacking and hydrogen bonding.Asn254was crucial to formhydrogenbonding. The reliability of the model was assessed through docking using both commercial and synthetic antagonists and an r2 of 0.70 was achieved. Our results show that molecular dynamics simulations of palmitoylated/ glycosylated, membrane-integrated human A2B;AR in its native environment is a possible approach and this model can be used for designing potent and selective A2B;AR antagonists. © Springer-Verlag 2012.
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