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 mod- els of human adenosine receptor A1 and A3 antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A1 pharmacophore model （A1-Hopyl） consists of four features： one hydrogen bond donor, one hydrophobic point and two ring aromatics, while the best A3 pharmacophore model （A3_Hopyl） also has four features： one hydrogen bond ac- ceptor, one hydrophobic point and two ring aromatics. The correlation coefficients were 0.840 for A1 test set with 146 diverse compounds and 0.827 for A3 test set with 238 diverse compounds. In the simulated virtual screening experiments, high en- richment factors of 6.51 and 6.90 were obtained for A1_Hopyl and A3_Hopyl models, respectively. Moreover, two models also showed high subtype-selectivity in the simulated virtual screening experiments. These results could be helpful for the dis- covery of novel potent and selective A1 and A3 antagonists.