Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists

Adenosine receptors are promising therapeutic targets in drug discovery. In this study, three-dimensional pharmacophore models of human adenosine receptor A(1) and A(3) antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A(1) pharmacophore model (A(1)_Hopy1) consists of four features: one hydrogen bond donor, one hydrophobic point and two ring aromatics, while the best A(3) pharmacophore model (A(3)_Hopy1) also has four features: one hydrogen bond acceptor, one hydrophobic point and two ring aromatics. The correlation coefficients were 0.840 for A(1) test set with 146 diverse compounds and 0.827 for A(3) test set with 238 diverse compounds. In the simulated virtual screening experiments, high enrichment factors of 6.51 and 6.90 were obtained for A(1)_Hopy1 and A(3)_Hopy1 models, respectively. Moreover, two models also showed high subtype-selectivity in the simulated virtual screening experiments. These results could be helpful for the discovery of novel potent and selective A(1) and A(3) antagonists.