3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists

Three-dimensional pharmacophore models were generated for A(2A) and A(2B) adenosine receptors (ARs) based on highly selective A(2A) and A(2B) antagonists using the Catalyst program. The best pharmacophore model for selective A(2A) antagonists (Hypo-A(2A)) was obtained through a careful validation process. Four features contained in Hypo-A(2A) (one ring aromatic feature (R, one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A(2A) AR selectivity. The best pharmacophore model for selective A(2B) antagonists (Hypo-A(2B)) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A(2B) antagonists training set. Hypo-A(2B) also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A(2B) AR binding affinity and are essential for A(2B) selectivity. Both A(2A) and A(2B) pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.