Ligand-based and receptor-based methods were used to investigate the binding modes of human adenosine A(2B) antagonists. At first, pharmacophore models were developed based on 140 diverse A(2B) antagonists from literature. Meanwhile, the structural model of A(2B) receptor was built up based on the crystal structure of human A(2A) receptor and validated by Induced Fit docking, Glide-XP and Glide-SP docking. Two models matched each other very well and some important implications were hence obtained. The residues of Phe173 and Glu174 in the second extracellular loop and Asn254 were crucial to the antagonists binding to form pi-pi stacking and hydrogen-bonding interactions. These findings would be very helpful for the discovery of novel and potent A(2B) antagonists.
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