Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents.

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.

Synthesis, biological evaluation and molecular docking studies of 2-piperazin-1-yl-quinazolines as platelet aggregation inhibitors and ligands of integrin αIIbβ3.

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 αIIbβ3 integrin in a suspension of washed human platelets. The key αIIbβ3 protein-ligand interactions were determined in docking experiments and some correlations have been observed between values of the affinity and docking scores.

Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3 as Antiplatelet Agents.

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.

Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ₃.

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 αIIbβ₃. Molecular docking of RGD mimetics to αIIbβ₃ receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores.

RGD mimetics containing phthalimidine fragment as novel ligands of fibrinogen receptor.

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)β(3) integrin in a suspension of washed human platelets. The key α(IIb)β(3) protein-ligand interactions were determined in docking experiments.

Derivatives of tetrahydroisoquinoline: synthesis and initial evaluation of novel non-peptide antagonists of the alpha(IIb)beta(3)-integrin.

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.

Derivatives of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid as novel fibrinogen receptor antagonists.

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.

Novel fibrinogen receptor antagonists--RGDF mimetics, 4-(1,2,3,4-tetrahydro-isoquinoline-7-yl)amino-4-oxo-butyric acid derivatives.

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.

Derivatives of 7-amino-1,2,3,4-tetrahydroisoquinoline and isophthalic acids as novel fibrinogen receptor antagonists.

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.

Novel fibrinogen receptor antagonists. RGDF mimetics, derivatives of 4-(isoindoline-5-yl)amino-4-oxobutyric acid.

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.

Synthesis and antiaggregatory activity of RGD-peptidomimetics based on 4-oxo-4-(piperazine-1-yl)butyric acid as Arg-mimetic.

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.