title: Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3 as Antiplatelet Agents.
abstract: 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).
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Pavel G
authors.initials: PG
authors.lastname: Polishchuk
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Georgiy V
authors.initials: GV
authors.lastname: Samoylenko
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.|Laboratory of Chemoinformatics (UMR 7140 CNRS/UniStra), University of Strasbourg , 1, rue B. Pascal, Strasbourg 67000, France.
authors.forename: Tetiana M
authors.initials: TM
authors.lastname: Khristova
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Krysko
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Kabanova
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Kabanov
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Kornylov
authors.affiliation: Laboratory of Chemoinformatics (UMR 7140 CNRS/UniStra), University of Strasbourg , 1, rue B. Pascal, Strasbourg 67000, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Klimchuk
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Andronati
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Kuz'min
authors.affiliation: A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine , Lustdorfskaya doroga 86, Odessa 65080, Ukraine.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Krysko
authors.affiliation: Laboratory of Chemoinformatics (UMR 7140 CNRS/UniStra), University of Strasbourg , 1, rue B. Pascal, Strasbourg 67000, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Varnek
mesh_terms: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D057786:Peptidomimetics; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D054852:Small Molecule Libraries; C084961:arginyl-glycyl-aspartyl-phenylalanine