title: Discovery of novel antagonists of glycoprotein IIb/IIIa-mediated platelet aggregation through virtual screening.
abstract: The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking thrombus formation. RUC-2 is a novel glycoprotein IIb/IIIa inhibitor of adenosine-5'-diphosphate (ADP)-induced platelet aggregation, importantly which exhibits a unique mode of binding with respect to classical Arg-Gly-Asp (RGD)-based glycoprotein IIb/IIIa antagonists. To identify new chemotypes that inhibit glycoprotein IIb/IIIa-mediated platelet aggregation like RUC-2, we performed a combination of structure-based pharmacophore screening and structure-based virtual screening approach to screen over 7.3 million small molecules based on the RUC-2-glycoprotein IIb/IIIa crystal structure. Three of the eleven hit compounds identified by virtual screening showed promising activity with IC50 values between 16.9 and 90.6μmolL(-1) in a human platelet aggregation assay induced by ADP and thrombin. The binding conformations of these three were analyzed to provide a rationalization of their activity profile. These compounds may serve as potential novel scaffolds for further development of glycoprotein IIb/IIIa antagonists.
authors: First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Yawen
authors: Y
authors: Wang
authors: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, PR China.
authors: Yang
authors: Y
authors: Zhao
authors: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, PR China.
authors: Rui
authors: R
authors: Sun
authors: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, PR China.
authors: Wanjun
authors: W
authors: Kong
authors: College of Medicine, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Bing
authors: B
authors: Wang
authors: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, PR China.
authors: Guangde
authors: G
authors: Yang
authors: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, PR China. Electronic address: yipingli@mail.xjtu.edu.cn.
authors: Yiping
authors: Y
authors: Li
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical; D056004:Molecular Dynamics Simulation; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate
keywords: Glycoprotein IIb/IIIa receptor; Platelet aggregation; Small molecules; Structure-based pharmacophore screening; Structure-based virtual screening