Pharmacophore modeling of human adenosine receptor A2A antagonists

Three-dimensional pharmacophore models of human adenosine receptor A2A antagonists were developed based on 23 diverse compounds selected from a large number of A2A antagonists. The best pharmacophore model, Hypo1, contained five features: one hydrogen bond donor , three hydrophobic points and one ring aromatic. Its correlation coefficient, root mean square deviation, and cost difference values were 0.955, 0.921 and 84.4, respectively, suggested that the Hypo1 model was reasonable and reliable. This model was validated by three methods: a test set of 106 diverse compounds, a simulated virtual screening, and superimposition with the crystal structure of A2A receptor. The results showed that Hypo1 was not only in agreement with the A2A crystal structure and literature reports, but also well identified active A2A antagonists from the virtual database. This methodology provides helpful information and a robust tool for the discovery of potent A2A antagonists.