ABSTRACT
This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.
Subject(s)
Antiviral Agents/pharmacology , DNA/drug effects , Vesicular stomatitis Indiana virus/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Blood Platelets/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Blood Platelets/cytology , Blood Platelets/metabolism , Humans , Ligands , Molecular Docking Simulation , Piperazines/chemistry , Piperazines/pharmacology , Platelet Aggregation/drug effectsABSTRACT
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).
Subject(s)
Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Chemistry Techniques, Synthetic , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Docking Simulation , Oligopeptides/chemistry , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
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.
Subject(s)
Drug Design , Phthalimides/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Receptors, Fibrinogen/antagonists & inhibitors , Arginine/analogs & derivatives , Arginine/metabolism , Blood Platelets/metabolism , Drug Evaluation, Preclinical , Fibrinogen/metabolism , Fluorescein-5-isothiocyanate/metabolism , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Ligands , Oligopeptides/chemistry , Oligopeptides/metabolism , Platelet Aggregation Inhibitors/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein Binding , Receptors, Fibrinogen/metabolism , Software , Stereoisomerism , Structure-Activity Relationship , Tirofiban , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Tyrosine/metabolismABSTRACT
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.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tetrahydroisoquinolines/chemistry , Fibrinogen/chemistry , Fluorescein-5-isothiocyanate/chemistry , Humans , Oligopeptides/chemistry , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein Binding , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacologyABSTRACT
It has been proposed a novel method for obtaining of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid as Arg-mimetic within the framework of search for novel fibrinogen receptor antagonists. New alpha (IIb)beta(3) antagonists were prepared on a base of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid. Their high antiaggregatory activities in a human platelet rich plasma and ability to block FITC-Fg binding to alpha (IIb)beta(3) on washed human platelets were estimated.
Subject(s)
Receptors, Fibrinogen/antagonists & inhibitors , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Blood Platelets/drug effects , Blood Platelets/metabolism , Fibrinogen/metabolism , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Oligopeptides/antagonists & inhibitors , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Platelet-Rich Plasma/drug effects , Protein Binding/drug effects , Receptors, Fibrinogen/metabolism , Tetrahydroisoquinolines/chemistryABSTRACT
Two novel RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydro-isoquinoline-7-yl)amino-4-oxo-butyric acid as a new 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 alphaIIbbeta3 on washed human platelets.
Subject(s)
Receptors, Fibrinogen/antagonists & inhibitors , Isoquinolines , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
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.
Subject(s)
Phthalic Acids/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Receptors, Fibrinogen/antagonists & inhibitors , Binding, Competitive/drug effects , Biological Assay , Drug Evaluation, Preclinical , Humans , Molecular Mimicry , Molecular Structure , Phthalic Acids/chemical synthesis , Phthalic Acids/chemistry , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Platelet Glycoprotein GPIIb-IIIa Complex/drug effects , Protein Binding/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Butyrates/chemical synthesis , Butyrates/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Receptors, Fibrinogen/antagonists & inhibitors , Butyrates/chemistry , Drug Evaluation, Preclinical , Humans , Indoles/chemistry , Isoindoles , Molecular Mimicry , Molecular Structure , Oligopeptides/chemistry , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Membrane Glycoproteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
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.