5 research outputs found
Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3
AbstractA series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics
Design, Virtual Screening, and Synthesis of Antagonists of α<sub>IIb</sub>β<sub>3</sub> as Antiplatelet Agents
This article describes design, virtual
screening, synthesis, and
biological tests of novel α<sub>IIb</sub>β<sub>3</sub> antagonists, which inhibit platelet aggregation. Two types of α<sub>IIb</sub>β<sub>3</sub> 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 α<sub>IIb</sub>β<sub>3</sub> and four ligands for its closed form followed by their synthesis
and <i>in vitro</i> tests. Experimental measurements of
affinity for α<sub>IIb</sub>β<sub>3</sub> and ability
to inhibit ADP-induced platelet aggregation (IC<sub>50</sub>) showed
that two designed ligands for the open form <b>4c</b> and <b>4d</b> (IC<sub>50</sub> = 6.2 nM and 25 nM, respectively) and
one for the closed form <b>12b</b> (IC<sub>50</sub> = 11 nM)
were more potent than commercial antithrombotic Tirofiban (IC<sub>50</sub> = 32 nM)