ABSTRACT
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.
Subject(s)
Biomimetic Materials/chemistry , Isoindoles/chemistry , Oligopeptides/chemistry , Phthalimides/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/chemistry , Binding Sites , Biomimetic Materials/metabolism , Biomimetic Materials/pharmacology , Crystallography, X-Ray , Fibrinogen/antagonists & inhibitors , Fibrinogen/metabolism , Humans , Isoindoles/metabolism , Isoindoles/pharmacology , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Oligopeptides/metabolism , Oligopeptides/pharmacology , Phthalimides/metabolism , Phthalimides/pharmacology , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein BindingABSTRACT
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.
