Synthesis, biological evaluation and molecular docking studies of 2-piperazin-1-yl-quinazolines as platelet aggregation inhibitors and ligands of integrin αIIbß3.

A series of 2-piperazin-1-yl-quinazolines were synthesized and evaluated for their antiaggregative activity. The synthesized small molecule compounds have potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to αIIbß3 integrin in a suspension of washed human platelets. The key αIIbß3 protein-ligand interactions were determined in docking experiments and some correlations have been observed between values of the affinity and docking scores.

Design, Virtual Screening, and Synthesis of Antagonists of αIIbß3 as Antiplatelet Agents.

This article describes design, virtual screening, synthesis, and biological tests of novel αIIbß3 antagonists, which inhibit platelet aggregation. Two types of αIIbß3 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 αIIbß3 and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for αIIbß3 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).