The Study Of Pharmacophore Modeling And Molecular Docking For Adenosine Receptor Antagonists

Adenosine receptors (ARs) belong to the superfamily of G protein-coupled receptors. Many physiological functions may be regulated by interaction of adenosine receptors. The AR antagonists have been considered a renewed target for potential treatment. Three-dimensional pharmacophore models were generated for four subtypes of ARs based on highly selective antagonists. The structure of A1AR transmembrane was built using homology modeling method. The binding modes of antagonists and their corresponding ARs were explored by molecular docking while important regions and residues in the active site were identified.The pharmacophore models of selective AR antagonists are capable of identifying corresponding highly potent antagonists and differentiating distinct subtypes of antagonists. Our A1 model consists of three features: one hydrogen bond acceptor (A) and two hydrophobic features (H) with excluded volume spheres. A_2A model for nonxanthine antagonists consists of one ring aromatic (R), one H, one A and one positively ionizable feature that seems to be essential for A_2A AR selectivity. A_2A model for xanthine antagonists consists of six features: two Ls, two Rs along with two Hs. A2B model consists of one H, one R and two As. A3 model with excluded volume spheres consists of one H, one R and three As.The A1 AR docking results predict there are three hydrophobic pockets, defined by a) Val181, Phe185, Phe186; b)Val87, Leu88, Tyr271, Ile274; c)Ile95, Val189, Ile274, Thr277. As for A_2A AR, Ile80, Ala81, Val84 and Leu85 might be involved in the interactions with antagonists. The A3 AR docking results suggest Ser181 forms hydrogen bond with antagonist, while His272 is essential forπ-πinteraction. Also, two hydrophobic pockets are delimited by a) Leu91, Val141, Pro145 and b)Leu264, Ile268.The results of our study provide useful information for optimizing the structure of AR antagonists and virtual screening, and therefore facilitate retrieve of structurally diverse compounds with desired biological activities.