title: Characterization of adenosine receptor in its native environment: insights from molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B) adenosine receptor.
abstract: Selective A(2B) 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 S-palmitoyl on the dynamic behavior of A(2B)AR model is explored. Homology modeling, molecular docking and molecular dynamics simulations were performed to explore structural features of A(2B)AR 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. Another MD 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 N-acetylglucosamine and S-palmitoyl moieties in its structure. Phe173 and Glu174 located in EL2 were determined to be involved in ligand-receptor interactions through π-π stacking and hydrogen bonding. Asn254 was crucial to form hydrogen-bonding. The reliability of the model was assessed through docking using both commercial and synthetic antagonists and an r(2) of 0.70 was achieved. Our results show that molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B)AR in its native environment is a possible approach and this model can be used for designing potent and selective A(2B)AR antagonists.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Mahboubeh
authors.initials: M
authors.lastname: Mansourian
authors.forename: Armin
authors.initials: A
authors.lastname: Madadkar-Sobhani
authors.forename: Karim
authors.initials: K
authors.lastname: Mahnam
authors.forename: Afshin
authors.initials: A
authors.lastname: Fassihi
authors.forename: Lotfollah
authors.initials: L
authors.lastname: Saghaie
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006031:Glycosylation; D006801:Humans; D054878:Lipoylation; D056004:Molecular Dynamics Simulation; D058915:Purinergic P1 Receptor Antagonists / Q000032:analysis / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000378:metabolism*; D040681:Structural Homology, Protein; D014584:User-Computer Interface
chemical_list: C547771:ADRA2B protein, human; D058915:Purinergic P1 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2