Design, Virtual Screening, and Synthesis of Antagonists of alpha(IIb)beta(3) as Antiplatelet Agents

作者：Polishchuk Pavel G; Samoylenko Georgiy V; Khristova Tetiana M; Krysko Olga L; Kabanova Tatyana A; Kabanov Vladimir M; Kornylov Alexander Yu; Klimchuk Olga; Langer Thierry; Andronati Sergei A; Kuz'min Victor E; Krysko Andrei A; Varnek Alexandre^*

来源：Journal of Medicinal Chemistry, 2015, 58(19): 7681-7694.

DOI：10.1021/acs.jmedchem.5b00865

This article describes design, virtual screening, synthesis, and biological tests of novel alpha(IIb)beta(3) antagonists, which inhibit platelet aggregation. Two types of and alpha(IIb)beta(3) 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 am,alpha(IIb)beta(3) and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for alpha(IIb)beta(3) 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).

• 出版日期2015-10-8