jm5b00865_si_002.csv (0.79 kB)
Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3 as Antiplatelet Agents
dataset
posted on 2015-10-08, 00:00 authored by Pavel G. Polishchuk, Georgiy V. Samoylenko, Tetiana
M. Khristova, Olga L. Krysko, Tatyana
A. Kabanova, Vladimir M. Kabanov, Alexander Yu. Kornylov, Olga Klimchuk, Thierry Langer, Sergei A. Andronati, Victor E. Kuz’min, Andrei A. Krysko, Alexandre VarnekThis 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).