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_IIbβ₃ as Antiplatelet Agents

This article describes design, virtual screening, synthesis, and biological tests of novel α_IIbβ₃ antagonists, which inhibit platelet aggregation. Two types of α_IIbβ₃ 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_IIbβ₃ and four ligands for its closed form followed by their synthesis and <i>in vitro</i> tests. Experimental measurements of affinity for α_IIbβ₃ and ability to inhibit ADP-induced platelet aggregation (IC₅₀) showed that two designed ligands for the open form <b>4c</b> and <b>4d</b> (IC₅₀ = 6.2 nM and 25 nM, respectively) and one for the closed form <b>12b</b> (IC₅₀ = 11 nM) were more potent than commercial antithrombotic Tirofiban (IC₅₀ = 32 nM)