Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most thrombin active-site inhibitors form a short antiparallel beta-strand with residues Ser214-Gly216. However, the Selectide Corp. inhibitors SEL2711 and SEL2770 bind to thrombin in a retro fashion, making a parallel beta-strand with Ser214-Gly216 similar to other retro-binding inhibitors. The crystallographic structures of thrombin-hirugen complexed with SEL2711 and SEL2770, which are isostructural with the binary thrombin-hirugen complex, have been determined and refined in the 9.0-2.1 A resolution range to final R values of 16.5 and 16.7%, respectively. The structures of the SEL2711 and SEL2770 complexes contain 131 and 104 water molecules, respectively, both of which correspond to occupancies of greater than 0.5. The L-4-amidinophenylalanyl residues of SEL2711 and SEL2770 are fixed at the S1 specificity site, utilizing favorable ionic and hydrogen-bonding interactions between the N atoms of the amidino group and the side-chain O atoms of Asp189. The Glu192 residue of thrombin adopts an extended conformation, which allows the L-cyclohexylglycyl residue in the P2 retro-binding position of the inhibitors to occupy a similar site to the P3 aspartate in thrombin platelet-receptor peptides bound to thrombin. The N-terminal acetyl group of both inhibitors is located in the S2 subsite, while the L-3-pyridyl-(3-methyl)-alanyl of SEL2711 and the L-(N,N-dimethyl)lysine of SEL2770 occupy the S3 D-Phe subsite of D-PheProArg chloromethyl ketone (PPACK) in the thrombin-PPACK complex. The two C-terminal residues of SEL2711 (leucine and proline) point into the solvent and have no electron density in the thrombin complex. Those of SEL2770 are also positioned into the solvent, but surprisingly produce weak electron density with high B values (<B> = 50 A2). Since the Selectide inhibitors are about 10(4) times more specific for factor Xa, modeling retro-binding to the latter suggests that the selectivity can be a consequence of interactions of the inhibitors in the S3-S4 binding subsites of factor Xa.
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PMID:Structures of thrombin retro-inhibited with SEL2711 and SEL2770 as they relate to factor Xa binding. 1008 9

Disseminated intravascular coagulation (DIC) is a frequent complication of meningococcal sepsis in children. Despite the availability of potent antibiotics, mortality in meningococcal disease remains high (about 10%), rising to 40% in patients presenting in severe shock and consecutive DIC. As the clinical course and the severity of manifestations of systemic meningococcal infections varies there is a need for early diagnosis of the infection and of the stage of coagulopathy in order to reduce the high mortality rate. Few and rapidly available parameters are needed to classify the wide spectrum of clinical and laboratory findings in patients with DIC. The parameters include partial thromboplastin time, prothrombin time, plasma levels of fibrinogen, antithrombin III (AT III), fibrin monomers and D-dimer concentration, fibrin degradation products and the thrombocyte count. Monitoring the course of hemostasis findings in 28 pediatric patients (age between 3 months and 8 years, mean 3.1 years) with systemic meningococcal infections we observed a change of coagulation parameters already in the first stages of the infection: A prolongation of partial thromboplastin time mean 69.1 sec (range 22-150 sec, normal 30-45 sec), a decrease of prothrombin time to 45.7% (range 13-71%, normal 70-100%) and of AT III to an average level of 70% (normal 85-125%) was found 1 to 4 (-6) hours after admission. The following deterioration of prothrombin time and partial thromboplastin time turned out to be statistically significant (p < 0.05, signed rank test). The monitoring of hemostasis parameters mentioned above made it to possible define the stage of coagulopathy and thus to start a stage related therapy. Treatment consisted of shock control by liquid substitution, compensation of metabolic acidosis, correction of clotting disorders (AT III and heparin in case of pre-DIC; AT III and fresh frozen plasma in case of advanced DIC), antibiotic treatment (beta-lactam antibiotics e.g. cefotaxime or ceftriaxone), and--when necessary--catecholamine infusions. An early assessment of the coagulation disorders in meningococcal disease can be based on few coagulation parameters. Thus an appropriate treatment can be arranged in order to prevent a fatal outcome of meningococcal sepsis and to protect against the development of a Water-house-Friderichsen-syndrome.
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PMID:Diagnosis and stage-related treatment of disseminated intravascular coagulation in meningococcal infections. 1040 13

Double rotational-echo double resonance (double REDOR) has been used to investigate the bound conformations of (13)C,(15)N,(19)F-labeled factor Xa inhibitors to bovine trypsin. Carbon-fluorine dipolar couplings were measured by (13)C{(19)F} REDOR with natural-abundance background interferences removed by (13)C{(15)N} REDOR. The conformations of the bound inhibitors were characterized by molecular dynamics (MD) simulations of binding restrained by double REDOR-determined intramolecular C-F distances. A symmetrical bisamidine inhibitor and an asymmetrical monoamidine-monoamine inhibitor of the same general shape had distinctly different conformations in the bound state. According to the MD models, these differences arise from specific interactions of the amidine and amine groups with the active-site residues of trypsin and nearby water molecules.
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PMID:Conformations of trypsin-bound amidine inhibitors of blood coagulant factor Xa by double REDOR NMR and MD simulations. 1050 39

The effects of guava leaf extract on the bleeding time and the three main mechanisms of haemostasis: vasoconstriction, platelet aggregation and blood coagulation, were investigated. The water extract of guava leaves did not shorten bleeding times in rats. Guava leaf extract potentiated the vascular muscle contraction induced in rabbits by phenylephrine, and when given alone it stimulated human platelet aggregation in vitro in a dose-dependent manner. On the other hand, it significantly prolonged blood coagulation; activated partial thromboplastin time (APTT) test (p < 0.05). The higher the concentration of the extract, the longer APTT was observed. Thus, a water extract of guava leaves showed ambiguous effects on the haemostatic system. Guava leaf extract did not affect bleeding times, it stimulated vasoconstriction and platelet aggregation but it inhibited blood coagulation. Therefore, guava leaf extract is not recommended as a haemostatic agent.
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PMID:Guava leaf extract and topical haemostasis. 1092 12

Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.
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PMID:Thiol repletion prevents venous thrombosis in rats by nitric oxide/prostacyclin-dependent mechanism: relation to the antithrombotic action of captopril. 1102 53

Three sets of molecular descriptors computable from connection table information are defined. These descriptors are based on atomic contributions to van der Waals surface area, log P (octanol/water), molar refractivity, and partial charge. The descriptors are applied to the construction of QSAR/QSPR models for boiling point, vapor pressure, free energy of solvation in water, solubility in water, thrombin/trypsin/factor Xa activity, blood-brain barrier permeability, and compound classification. The wide applicability of these descriptors suggests uses in QSAR/QSPR, combinatorial library design, and molecular diversity work.
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PMID:A widely applicable set of descriptors. 1114 63

Sulfated polysaccharides exhibit many biological properties such as antiviral and anticoagulant activities. Herein, we report the antiviral activity of sulfated galactans extracted from the red sea-weed Bostrychia montagnei against herpes simplex virus types 1 (strain F and the thymidine kinase-deficient strains Field and B2006) and 2 (strain G). Two crude extracts obtained with cold and hot water as well as some fractions obtained by anion exchange chromatography, inhibited significantly the replication of the different strains of herpesviruses as determined by plaque reduction assays. The inhibitory effect of the compounds studied here took place only when they were added during the adsorption period. They were found to be highly selective antiviral substances, causing no impairment of Vero cell viability. Furthermore, they had no direct inactivating effect on virions by incubation in a virucidal assay. The antiviral activity could be correlated with the molecular weight and sulfate content of the polysaccharides. Although sulfated polysaccharides are generally endowed with anticoagulant properties, the results of the activated partial thromboplastin time and the thrombine time assays indicated that the natural sulfated polysaccharides from Bostrychia montagnei have very low anticoagulant activity, confirming that there is no relation between the antiviral and anticoagulant properties.
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PMID:Inhibitory effect of sulfated galactans from the marine alga Bostrychia montagnei on herpes simplex virus replication in vitro. 1129 40

We describe a new serine protease inhibition motif in which binding is mediated by a cluster of very short hydrogen bonds (<2.3 A) at the active site. This protease-inhibitor binding paradigm is observed at high resolution in a large set of crystal structures of trypsin, thrombin, and urokinase-type plasminogen activator (uPA) bound with a series of small molecule inhibitors (2-(2-phenol)indoles and 2-(2-phenol)benzimidazoles). In each complex there are eight enzyme-inhibitor or enzyme-water-inhibitor hydrogen bonds at the active site, three of which are very short. These short hydrogen bonds connect a triangle of oxygen atoms comprising O(gamma)(Ser195), a water molecule co-bound in the oxyanion hole (H(2)O(oxy)), and the phenolate oxygen atom of the inhibitor (O6'). Two of the other hydrogen bonds between the inhibitor and active site of the trypsin and uPA complexes become short in the thrombin counterparts, extending the three-centered short hydrogen-bonding array into a tetrahedral array of atoms (three oxygen and one nitrogen) involved in short hydrogen bonds. In the uPA complexes, the extensive hydrogen-bonding interactions at the active site prevent the inhibitor S1 amidine from forming direct hydrogen bonds with Asp189 because the S1 site is deeper in uPA than in trypsin or thrombin. Ionization equilibria at the active site associated with inhibitor binding are probed through determination and comparison of structures over a wide range of pH (3.5 to 11.4) of thrombin complexes and of trypsin complexes in three different crystal forms. The high-pH trypsin-inhibitor structures suggest that His57 is protonated at pH values as high as 9.5. The pH-dependent inhibition of trypsin, thrombin, uPA and factor Xa by 2-(2-phenol)benzimidazole analogs in which the pK(a) of the phenol group is modulated is shown to be consistent with a binding process involving ionization of both the inhibitor and the enzyme. These data further suggest that the pK(a) of His57 of each protease in the unbound state in solution is about the same, approximately 6.8. By comparing inhibition constants (K(i) values), inhibitor solubilities, inhibitor conformational energies and corresponding structures of short and normal hydrogen bond-mediated complexes, we have estimated the contribution of the short hydrogen bond networks to inhibitor affinity ( approximately 1.7 kcal/mol). The structures and K(i) values associated with the short hydrogen-bonding motif are compared with those corresponding to an alternate, Zn(2+)-mediated inhibition motif at the active site. Structural differences among apo-enzymes, enzyme-inhibitor and enzyme-inhibitor-Zn(2+) complexes are discussed in the context of affinity determinants, selectivity development, and structure-based inhibitor design.
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PMID:A novel serine protease inhibition motif involving a multi-centered short hydrogen bonding network at the active site. 1129 54

The sulfated glycosaminoglycan heparin is an important anticoagulant, widely used to treat and to prevent arterial thrombosis. Heparin triggers conformational changes in, and the functional activation of, the serine proteinase inhibitor antithrombin. We investigated water-transfer reactions during the activation process to explore the possibility that functional interaction between antithrombin and sulfated glycosaminoglycans can be regulated by osmotic potentials. Volume of water transferred upon heparin binding was measured from differences in free energy change, Delta(Delta G), with osmotic stress, pi. Osmotic stress was induced with chemically inert probes that are geometrically excluded from the water-permeable spaces of antithrombin and from intermolecular spaces formed during the association reaction. The free energy change, Delta G, for the antithrombin/heparin interaction was calculated from the dissociation constant, determined by functional titrations of heparin with antithrombin at fixed concentrations of the coagulation protease factor Xa. The effect of osmotic stress was independent of the chemical nature of osmotic probes but correlated with their radius up to radius >17 A. In mixtures including a large and a small probe, the effect of the large probe was not modified by the small probe added at a large molar excess. With an osmotic probe of 4-A radius, the Delta(Delta G)/pi slope corresponds to a transfer of 119 +/- 25 water molecules to bulk solution on formation of the complex. Analytical characterization of water-permeable volumes in x-ray-derived bound and free antithrombin structures revealed complex surfaces with smaller hydration volumes in the bound relative to the free conformation. The residue distribution in, and atomic composition of, the pockets containing atoms from residues implicated in heparin binding were distinct in the bound versus free conformer. The results demonstrate that the heparin/antithrombin interaction is linked to net water transfer and, therefore, can be regulated in biological gels by osmotic potentials.
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PMID:Regulation of glycosaminoglycan function by osmotic potentials. Measurement of water transfer during antithrombin activation by heparin. 1167 28

Exposure to ultra-violet (UV)-C radiation is a frequently used method to prevent bacteria from invasion of blood-contact biomedical products. Potential damage induced by UV radiation to collagen is of concern due to the decay of bioactivity, considerably correlated with structural alterations. Our current investigation studies the collagen-bonded non-woven polypropylene (PP) fabric surface. In this experiment, antenna-coupling microwave plasma is utilized to activate PP fabric and then the sample is grafted with acrylic acid (AAc). Type III collagen is immobilized by using water soluble 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as coupling agent. The collagen-bonded samples with sample temperature ca. 4 degrees C are then exposed to UV-254nm radiation for different time intervals. By using fourier-transformed infrared with attenuated total reflection (FTIR-ATR) and XPS (X-ray photoelectron spectroscopy), we examine the chemical structures of samples with different treatments. Coomassie brilliant blue G250 method is utilized to quantify the immobilized collagen on the PP fabric surfaces. Blood-clotting effects are evaluated by activated partial thromboplastin time, thrombin time, and fibrinogen concentration tests. By means of cell counter and scanning electron microscopy we count red blood cells and platelets adhesion in the modified porous matrix. Our experimental results have demonstrated that with pAAc-grafting of ca. 173 microg cm(-2) and immobilized collagen of 80.5+/-4.7 microg cm(-2), for human plasma incubated samples of various intervals of UV-254 nm radiation, fibrinogen concentration decreases in human plasma, while platelets and red blood cells adhesions increase before UV radiation. However, the required time for thrombination shows significant change for UV radiation exposure of less than 20 h (alpha = 0.05). The decay of bioactivity for the UV-irradiated, collagen-bonded surfaces is thus evaluated. Surface analyses indicate that the decrease of R-COOH (derivated from grafted-pAAc or de-carboxylation of collagen), amides degradation (broken-NH), and phenylalanine scission (terminated by -OH, tyrosine formation) may gradually damage collagen by increasing the intervals of UV radiation. These effects considerably influence the bioactivity of the collagen-bonded fabric. The XPS measurements of C 1s core levels at 288.4 eV (O = C-NH) and at 289.1 eV (O = C-O) illustrate significant decreases of intensity after radiation time ca. 44 h. It is clear that UV-254 nm radiation exposure for ca. 20 h has the potential impact to moderate the bioactivities of collagen and therefore act as a vital factor to accelerate biodegradation.
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PMID:Assessment and characterization of degradation effect for the varied degrees of ultra-violet radiation onto the collagen-bonded polypropylene non-woven fabric surfaces. 1176 56


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