Docking-based virtual screening of potential human P2Y12 receptor antagonists  

作　　者：Hua Chen Xianchi Dong Minyun Zhou Haiming Shi Xinping Luo 

机构地区：[1]Department of Cardiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China [2]State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [3]Graduate School of Chinese Academy of Sciences, Shanghai 200031, China

出　　处：《Acta Biochimica et Biophysica Sinica》2011年第5期400-408,共9页生物化学与生物物理学报（英文版）

摘　　要：Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor, and its antagonists have been widely developed as anticoagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved satisfactory antithrombotic effects, leaving room for further improvement. To identify new chemical compounds as potential anticoagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo β1 adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds that might have high binding affinity to P2Y12. Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development.Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor, and its antagonists have been widely developed as anticoagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved satisfactory antithrombotic effects, leaving room for further improvement. To identify new chemical compounds as potential anticoagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo β1 adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds that might have high binding affinity to P2Y12. Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development.

关 键 词：P2Y12 homology modeling virtual screening ANTI-COAGULATION 

分 类 号：Q[生物学]