Design, Virtual Screening, and Synthesis of Antagonists of α IIb β 3 as Antiplatelet Agents
| Autor: | Tatyana A. Kabanova, Tetiana M. Khristova, Georgiy V. Samoylenko, Olga L. Krysko, Sergei A. Andronati, Alexandre Varnek, V. M. Kabanov, Victor E. Kuz’min, Alexander Yu. Kornylov, Thierry Langer, Olga Klimchuk, Pavel G. Polishchuk, A. A. Krysko |
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| Přispěvatelé: | Chimie de la matière complexe (CMC), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Strasbourg, Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Peptidomimetic Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Chemistry Techniques Synthetic Platelet Glycoprotein GPIIb-IIIa Complex Molecular Docking Simulation Small Molecule Libraries Inhibitory Concentration 50 Drug Discovery Humans Virtual screening Chemistry Combinatorial chemistry Docking (molecular) Drug Design Molecular Medicine Platelet aggregation inhibitor Peptidomimetics Pharmacophore Oligopeptides Platelet Aggregation Inhibitors [CHIM.CHEM]Chemical Sciences/Cheminformatics |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2015, 58 (19), pp.7681-7694. ⟨10.1021/acs.jmedchem.5b00865⟩ |
| ISSN: | 0022-2623 1520-4804 |
| Popis: | This 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). |
| Databáze: | OpenAIRE |
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