Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists  

作　　者：XU ZheJun CHENG FeiXiong LI Jie ZHOU YaDi SU Ni LI WeiHua LIU GuiXia TANG Yun 

机构地区：[1]Department of Pharmaeeutical Sciences,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China

出　　处：《Science China Chemistry》2012年第11期2407-2418,共12页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China (21072059);the Program for New Century Excellent Talents in University (NCET-08-0774);the 111 Project (B07023);the Shanghai Committee of Science and Technology (11DZ2260600);the Fundamental Research Funds for the Central Universities (WY1113007);the National S&T Major Project of China ( 2009ZX09501-001)

摘　　要：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.Adenosine receptors are promising therapeutic targets in drug discovery. In this study, three-dimensional pharmacophore models of human adenosine receptor A1 and A3 antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A1 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 (A3 _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 A3 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 A3 _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 A3 antagonists.

关 键 词：pharmacophore modeling adenosine receptors ANTAGONISTS enrichment factor simulated virtual screening 

分 类 号：TQ463.54[化学工程—制药化工] TQ457.2