Discovery of novel antagonists of glycoprotein IIb/IIIa-mediated platelet aggregation through virtual screening. Issue 6 (15th March 2015)

• Record Type: Journal Article
• Authors: Wang, Yawen; Zhao, Yang; Sun, Rui; Kong, Wanjun; Wang, Bing; Yang, Guangde; Li, Yiping
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 6(2015)
• Page Start: 1249
• Page End: 1253
• Publication Date: 2015-03-15
• Subjects: Glycoprotein IIb/IIIa receptor -- Structure-based pharmacophore screening -- Structure-based virtual screening -- Platelet aggregation -- Small molecules; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.053
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 90.6 μmol L −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.