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J Med Chem. 2015 Oct 8;58(19):7681-94. doi: 10.1021/acs.jmedchem.5b00865. Epub 2015 Sep 25.

Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3 as Antiplatelet Agents.

Author information

1
A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
2
Laboratory of Chemoinformatics (UMR 7140 CNRS/UniStra), University of Strasbourg , 1, rue B. Pascal, Strasbourg 67000, France.
3
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.

Abstract

This article describes design, virtual screening, synthesis, and biological tests of novel αIIbβ3 antagonists, which inhibit platelet aggregation. Two types of αIIbβ3 antagonists were developed: those binding either closed or open form of the protein. At the first step, available experimental data were used to build QSAR models and ligand- and structure-based pharmacophore models and to select the most appropriate tool for ligand-to-protein docking. Virtual screening of publicly available databases (BioinfoDB, ZINC, Enamine data sets) with developed models resulted in no hits. Therefore, small focused libraries for two types of ligands were prepared on the basis of pharmacophore models. Their screening resulted in four potential ligands for open form of αIIbβ3 and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for αIIbβ3 and ability to inhibit ADP-induced platelet aggregation (IC50) showed that two designed ligands for the open form 4c and 4d (IC50 = 6.2 nM and 25 nM, respectively) and one for the closed form 12b (IC50 = 11 nM) were more potent than commercial antithrombotic Tirofiban (IC50 = 32 nM).

PMID:
26367138
DOI:
10.1021/acs.jmedchem.5b00865
[Indexed for MEDLINE]

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