RESUMO
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).
Assuntos
Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
The novel RGD mimetics with phthalimidine central fragment were synthesized with the use of 4-piperidine-4-yl-butyric, 4-piperidine-4-yl-benzoic, 4-piperazine-4-yl-benzoic and 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acids as surrogates of Arg motif. The synthesized compounds potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to α(IIb)ß(3) integrin in a suspension of washed human platelets. The key α(IIb)ß(3) protein-ligand interactions were determined in docking experiments.
Assuntos
Desenho de Fármacos , Ftalimidas/síntese química , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Receptores de Fibrinogênio/antagonistas & inibidores , Arginina/análogos & derivados , Arginina/metabolismo , Plaquetas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fibrinogênio/metabolismo , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Ligantes , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Inibidores da Agregação Plaquetária/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica , Receptores de Fibrinogênio/metabolismo , Software , Estereoisomerismo , Relação Estrutura-Atividade , Tirofibana , Tirosina/análogos & derivados , Tirosina/química , Tirosina/metabolismoRESUMO
The novel fibrinogen receptor antagonists containing fragments of 7-amino-1,2,3,4-tetrahydroisoquinoline and isophthalic acids were synthesized and successfully tested for their ability to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alpha(IIb)beta(3) on washed human platelets.
Assuntos
Ácidos Ftálicos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Receptores de Fibrinogênio/antagonistas & inibidores , Ligação Competitiva/efeitos dos fármacos , Bioensaio , Avaliação Pré-Clínica de Medicamentos , Humanos , Mimetismo Molecular , Estrutura Molecular , Ácidos Ftálicos/síntese química , Ácidos Ftálicos/química , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The novel RGDF mimetics 9a and 9b were synthesized with the use of 4-(isoindoline-5-yl)amino-4-oxobutyric acid as a surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alpha(IIb)beta(3) on washed human platelets.