ORIGINAL PAPER Characterization of adenosine receptor in its native environment: insights from molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A 2B adenosine receptor Mahboubeh Mansourian & Armin Madadkar-Sobhani & Karim Mahnam & Afshin Fassihi & Lotfollah Saghaie Received: 16 December 2011 / Accepted: 3 April 2012 / Published online: 9 May 2012 # Springer-Verlag 2012 Abstract Selective A 2B receptor antagonists and agonists may play a role in important pathologies such as gastrointes- tinal, neurological (i.e., Alzheimer disease and dementia) and hypersensitive disorders (i.e., asthma), diabetes, atherosclero- sis, 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 ex- plored. Homology modeling, molecular docking and molecu- lar 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 environ- ment is a possible approach and this model can be used for designing potent and selective A 2B AR antagonists. Keywords A 2B AR . GPCR . Molecular docking . Molecular dynamics simulation . Post-translational modifications Introduction Adenosine is an endogenous purine nucleoside widely dis- tributed in mammalian tissues. The first recorded report describing evidence for an adenosine receptor dates back to 1976. Up to now four adenosine receptor (AR) subtypes, A 1 ,A 2A ,A 2B , and A 3 have been characterized. The A 2A AR and A 2B AR stimulate adenylyl cyclase through coupling to the G s protein resulting in an increase in cyclic adenosine mono phosphate (cAMP) levels, whereas the A 1 and A 3 subtypes inhibit adenylyl cyclase via coupling to G i protein thus leading to diminishment of cAMP. Growing evidence Electronic supplementary material The online version of this article (doi:10.1007/s00894-012-1427-y) contains supplementary material, which is available to authorized users. M. Mansourian : A. Fassihi (*) : L. Saghaie Department of Medicinal Chemistry, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran e-mail: fassihi@pharm.mui.ac.ir A. Madadkar-Sobhani Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran A. Madadkar-Sobhani (*) Life Sciences Department, Barcelona Supercomputing Center (BSC), 08034 Barcelona, Spain e-mail: amadadka@bsc.es K. Mahnam Biology Department, Faculty of Science, Shahrekord University, Shahrekord, Iran J Mol Model (2012) 18:4309–4324 DOI 10.1007/s00894-012-1427-y