RESUMO
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.
Assuntos
Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Plaquetas/citologia , Plaquetas/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Piperazinas/química , Piperazinas/farmacologia , Agregação Plaquetária/efeitos dos fármacosRESUMO
A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born's method was shown to be due to inhibition of fibrinogen binding to αIIbß3. Molecular docking of RGD mimetics to αIIbß3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.
Assuntos
Materiais Biomiméticos/química , Isoindóis/química , Oligopeptídeos/química , Ftalimidas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Sítios de Ligação , Materiais Biomiméticos/metabolismo , Materiais Biomiméticos/farmacologia , Cristalografia por Raios X , Fibrinogênio/antagonistas & inibidores , Fibrinogênio/metabolismo , Humanos , Isoindóis/metabolismo , Isoindóis/farmacologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Ftalimidas/metabolismo , Ftalimidas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação ProteicaRESUMO
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 RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-4-oxobutyric or 5-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-5-oxopentanoic acids 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.
Assuntos
Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tetra-Hidroisoquinolinas/química , Fibrinogênio/química , Fluoresceína-5-Isotiocianato/química , Humanos , Oligopeptídeos/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
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
A scheme of synthesis of previously obtained RGDF-peptidomimetic-4-oxo-4-(piperazine-1-yl)butyrylglycyl-D,L-beta-phenyl-beta-alanine (I), was simplified. The novel RGDF-peptidomimetic -4-oxo-4-piperazine-1-yl)butyryl-glycyl-L-aspartyl-L-phenylalanine (II) was synthesized with the use of 4-oxo-4-(piperazine-1-yl)butyric acid as arginyl mimetic. The obtained pseudopeptides were able to inhibit both platelet aggregation in human blood and binding of fibrinogen to its receptor.