34 research outputs found
New Synthetic Thrombin Inhibitors: Molecular Design and Experimental Verification
BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications
The nonperturbative functional renormalization group and its applications
The renormalization group plays an essential role in many areas of physics,
both conceptually and as a practical tool to determine the long-distance
low-energy properties of many systems on the one hand and on the other hand
search for viable ultraviolet completions in fundamental physics. It provides
us with a natural framework to study theoretical models where degrees of
freedom are correlated over long distances and that may exhibit very distinct
behavior on different energy scales. The nonperturbative functional
renormalization-group (FRG) approach is a modern implementation of Wilson's RG,
which allows one to set up nonperturbative approximation schemes that go beyond
the standard perturbative RG approaches. The FRG is based on an exact
functional flow equation of a coarse-grained effective action (or Gibbs free
energy in the language of statistical mechanics). We review the main
approximation schemes that are commonly used to solve this flow equation and
discuss applications in equilibrium and out-of-equilibrium statistical physics,
quantum many-particle systems, high-energy physics and quantum gravity.Comment: v2) Review article, 93 pages + bibliography, 35 figure