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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Wang Y,Zhao Y,Sun R,Kong W,Wang B,Yang G,Li Y

doi

10.1016/j.bmcl.2015.01.053

subject

Has Abstract

pub_date

2015-03-15 00:00:00

pages

1249-53

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00065-7

journal_volume

25

pub_type

杂志文章

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