Acta Phys. -Chim. Sin. ›› 2015, Vol. 31 ›› Issue (8): 1584-1596.doi: 10.3866/PKU.WHXB201505253

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

Comparison of the Selectivity of Human Adenosine Receptor Antagonists Based on Structure and Pharmacophore Features

Ling-Xiao. ZENG,Xin-Ran. LI,Hong-Wei. JIN,Zhen-Ming. LIU*(),Liang-Ren. ZHANG*()   

  • Received:2015-04-17 Published:2015-08-12
  • Contact: Zhen-Ming. LIU,Liang-Ren. ZHANG;
  • Supported by:
    the National Natural Science Foundation of China(21272017);Doctoral Fund of Ministry of Education of China(20090001120049)


Adenosine receptors (ARs) are crucial therapeutic targets, and selective adenosine receptor antagonists are promising for numerous therapeutic applications. In this study, three dimensional models of human adenosine A1, A2B, and A3 receptors (A1AR, A2BAR, A3AR, respectively) were generated by homology modeling. In addition, pharmacophore models of the antagonists of four human adenosine receptor subtypes were developed using the LigandScout 3.12 program. Furthermore, Induced Fit Docking module of Schrödinger program was implemented to investigate receptor-ligand interactions. The results show that because of the subfamily-wide conservation of the core pocket residues, the ligand binding pockets of the three raw AR homology models are extremely similar, which poses challenges for subtype selective ligand recognition. However, the pharmacophore models of the four AR subtypes differ in pharmacophore features and spatial configuration, which are also consistent with previous site-directed mutagenesis studies. This indicates that binding site optimization is a crucial step in model generation, and the distributions for a set of pharmacophore features in ligand-based pharmacophore, including hydrogen bond acceptors, hydrogen bond donors, hydrophobic centroids, and aromatic rings, can reflect the position and direction characterization of hydrogen bonds and hydrophobic cavities, which aid identification and characterization of binding sites. This study may provide a significant theoretical foundation for further raw model optimization in homology modeling and discovery of novel selective human adenosine receptor antagonists.

Key words: Pharmacophore, Human adenosine receptor, Antagonist, Selectivity


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