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:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a binding free energy function that consists of force field terms supplemented by solvation terms. We used this function to calibrate the solvation model along with the binding interaction terms in a self-consistent manner. The motivation for this approach was that the solute dielectric-constant dependence of calculated hydration gas-to-water transfer free energies is markedly different from that of binding free energies (J. Comput. Chem. 2003, 24, 954). Hence, we sought to calibrate directly the solvation terms in the context of a binding calculation. The five parameters of the model were systematically scanned to best reproduce the absolute binding free energies for a set of 99 protein-ligand complexes. We obtained a mean unsigned error of 1.29 kcal/mol for the predicted absolute binding affinity in a parameter space that was fairly shallow near the optimum. The lowest errors were obtained with solute dielectric values of Din = 20 or higher and scaling of the intermolecular van der Waals interaction energy by factors ranging from 0.03 to 0.15. The high apparent Din and strong van der Waals scaling may reflect the anticorrelation of the change in solvated potential energy and configurational entropy, that is, enthalpy-entropy compensation in ligand binding (Biophys. J. 2004, 87, 3035-3049). Five variations of preparing the protein-ligand data set were explored in order to examine the effect of energy refinement and the presence of bound water on the calculated results. We find that retaining water in the final protein structure used for calculating the binding free energy is not necessary to obtain good results; that is the continuum solvation model is sufficient. Virtual screening enrichment studies on estrogen receptor and thymidine kinase showed a good ability of the binding free energy function to recover true hits in a collection of decoys.
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PMID:Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. 1723 57

We report the development and validation of a novel suite of programs, FITTED 1.0, for the docking of flexible ligands into flexible proteins. This docking tool is unique in that it can deal with both the flexibility of macromolecules (side chains and main chains) and the presence of bridging water molecules while treating protein/ligand complexes as realistically dynamic systems. This software relies on a genetic algorithm to account for the flexibility of the two molecules as well as the location of bridging water molecules. In addition, FITTED 1.0 features a novel application of a switching function to retain or displace key water molecules from the protein-ligand complexes. Two independent modules, ProCESS and SMART, were developed to set up the proteins and the ligands prior to the docking stage. Validation of the accuracy of the software was achieved via the application of FITTED 1.0 to the docking of inhibitors of HIV-1 protease, thymidine kinase, trypsin, factor Xa, and MMP to their respective proteins.
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PMID:Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0. 1730 29

The site-specific conjugation of metal chelating systems to biologically relevant molecules is an important contemporary topic in bioinorganic and bioorganometallic chemistry. In this work, we have used the CuI-catalyzed cycloaddition of azides and terminal alkynes to synthesise novel ligand systems, in which the 1,2,3-triazole is an integral part of the metal chelating system. A diverse set of bidentate alkyne building blocks with different aliphatic and aromatic backbones and various donor groups were prepared. The bidentate alkynes were reacted with benzyl azide in the presence of a catalytic amount of CuI to form tridentate model ligands. The chelators were reacted with [ReBr3(CO)3]2- to form well-defined and stable complexes with different overall charges, structures and hydrophilicities. In all cases tridentate coordination of the ligands, including through N3 of the 1,2,3-triazole ring, was observed. The ligand systems could also be quantitatively radiolabelled with the precursor [99 mTc (H2O)3(CO)3]+ at low ligand concentrations. Similarly the alkynes were reacted with an azido thymidine derivative to form a series of compounds, which could be radiolabelled in situ to form single products. Subsequent incubation of the neutral and cationic organometallic 99 mTc thymidine derivatives with human cytosolic thymidine kinase, a key enzyme in tumour proliferation, revealed that only the neutral compounds maintained substrate activity towards the enzyme. Bioconjugation, radiolabelling and enzymatic reactions were successfully performed in a matter of hours. Thus, click chemistry provides an elegant method for rapidly functionalising a biologically relevant molecule with a variety of efficient metal chelators suitable for (radio)labelling with the M(CO)3 core (M=99 mTc, Re), to offer new potential for technetium-99 m in clinical and preclinical tracer development.
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PMID:"Click-to-chelate": design and incorporation of triazole-containing metal-chelating systems into biomolecules of diagnostic and therapeutic interest. 1849 20

Longitudinal and transverse relaxations in the rotating frame, with characteristic time constants T1rho and T2rho, respectively, have potential to provide unique MRI contrast in vivo. On-resonance spin-lock T1rho with different spin-lock field strengths and adiabatic T2rho with different radiofrequency-modulation functions were measured in BT4C gliomas treated with Herpes Simplex Virus thymidine kinase (HVS-tk) gene therapy causing apoptotic cell death. These NMR tools were able to discriminate different treatment responses in tumor tissue from day 4 onward. An equilibrium two-site exchange model was used to calculate intrinsic parameters describing changes in water dynamics. Observed changes included increased correlation time of water associated with macromolecules and a decreased fractional population of this pool. These results are consistent with destructive intracellular processes associated with cell death and the increase of extracellular space during the treatment. Furthermore, association between longer exchange correlation time and decreased pH during apoptosis is discussed. In this study, we demonstrated that T1rho and T2rho MR imaging are useful tools to quantify early changes in water dynamics reflecting treatment response during gene therapy.
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PMID:Water spin dynamics during apoptotic cell death in glioma gene therapy probed by T1rho and T2rho. 1850 97

Diacetyl (2,3-butanedione) is a yellowish liquid that is usually mixed with other ingredients to produce butter flavor or other flavors in a variety of food products. Inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Recent findings have shown irreversible obstructive lung disease among workers not only in the microwave popcorn industry, but also in flavoring manufacture, and in chemical synthesis of diacetyl, a predominant chemical for butter flavoring. It has been reported that perfluorochemicals utilized in food packaging are migrating into foods and may be sources of oral exposure. Relatively small quantities of perfluorochemicals are used in the manufacturing of paper or paperboard that is in direct contact with food to repel oil or grease and water. Because of recent concerns about perfluorochemicals such as those found on microwave popcorn bags (e.g. Lodyne P208E) and diacetyl in foods, we evaluated both compounds for mutagenicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Lodyne P208E was less toxic than diacetyl and did not induce a mutagenic response. Diacetyl induced a highly mutagenic response in the L5178Y mouse lymphoma mutation assay in the presence of human liver S9 for activation. The increase in the frequency of small colonies in the assay with diacetyl indicates that diacetyl causes damage to multiple loci on chromosome 11 in addition to functional loss of the thymidine kinase locus.
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PMID:Evaluation of the butter flavoring chemical diacetyl and a fluorochemical paper additive for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. 1858 28

The measurement of water diffusion by diffusion-weighted MRI (DWI) in vivo offers a non-invasive method for assessing tissue responses to anti-cancer therapies. The pathway of cell death after anti-cancer treatment is often apoptosis, which leads to accumulation of mobile lipids detectable by (1)H MRS in vivo. However, it is not known how these discrete MR markers of cell death relate to each other. In a rodent tumour model [i.e. ganciclovir-treated herpes simplex thymidine kinase (HSV-tk) gene-transfected BT4C gliomas], we studied the interrelationships between water diffusion (Trace{D}) and mobile lipids during apoptosis. Water diffusion and water-referenced concentrations of mobile lipids showed clearly increasing and interconnected trends during treatment. Of the accumulating (1)H MRS-visible lipids, the fatty acid --CH==CH-- groups and cholesterol compounds showed the strongest associations with water diffusion (r(2) = 0.30; P < 0.05 and r(2) = 0.48; P < 0.01, respectively). These results indicate that the tumour histopathology and apoptotic processes during tumour shrinkage can be interrelated in vivo by DWI of tissue water and (1)H MRS of mobile lipids, respectively. However, there is considerable individual variation in the associations, particularly at the end of the treatment period, and in the relative compositions of the accumulating NMR-visible lipids. The findings suggest that the assessment of individual treatment response in vivo may benefit from combining DWI and (1)H MRS. Absolute and relative changes in mobile lipids may indicate initiation of tumour shrinkage even when changes in tissue water diffusion are still small. Conversely, greatly increased water diffusion probably indicates that substantial cell decomposition has taken place in the tumour tissue when the (1)H MRS resonances of mobile lipids alone can no longer give a reliable estimate of tissue conditions.
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PMID:Monitoring of gliomas in vivo by diffusion MRI and (1)H MRS during gene therapy-induced apoptosis: interrelationships between water diffusion and mobile lipids. 1900 68

Liver fibrosis results from sustained wound healing response to chronic liver injury. Liver cirrhosis, the end stage of the fibrotic process, is characterized by disruption of the entire liver architecture and reduced hepatocyte regenerative ability. Hepatic stimulator substance (HSS) is a liver-specific growth factor triggering hepatocyte proliferation in vitro and in vivo. Previous studies have indicated the involvement of HSS in animal models of acute liver injury. The aim of the present study was to investigate the involvement of HSS in the process of fibrosis and cirrhosis induction. Liver fibrosis and cirrhosis were induced in rats by thioacetamide (TAA) administration (300 mg/l) in the drinking water for 3 months, and animals were killed at 0, 1, 2, and 3 months of treatment. TAA administration resulted in progressively increasing liver fibrosis, leading to the onset of cirrhosis at the end of the experimental time. HSS was continuously produced during the course of fibrosis and cirrhosis induction, peaking at the 2nd month of TAA treatment, coinciding with markers of hepatic proliferative capacity, as thymidine kinase activity and DNA biosynthesis. Significantly reduced HSS activity was noted in cirrhotic liver (3rd month). In this case, the exogenous HSS administration during the 3rd month of TAA treatment suppressed the onset of liver cirrhosis, stimulating the hepatic regenerative capacity. Our data indicate the active participation of HSS in the process of fibrosis and cirrhosis induction post-TAA treatment in rats, suggesting also the beneficial effect of HSS treatment against cirrhosis induction with future possible clinical implications.
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PMID:Involvement of hepatic stimulator substance in experimentally induced fibrosis and cirrhosis in the rat. 1908 14

Aciclovir (ACV) is the drug of choice against herpes simplex virus type 1 (HSV-1) infection. However, its limited solubility in water and limited oral bioavailability represent the main limitations of this drug. Utilising a plaque reduction assay, this study assessed the antiherpetic activity of a new homodimer of ACV (ACVp(2)ACV) with a higher water solubility. ACVp(2)ACV markedly inhibited HSV-1 replication in Vero cells [50% effective concentration (EC(50)) of 2.8 microM vs. 6.6 microM for ACV] and was non-toxic in the cells at concentrations <or= 15 microM. ACVp(2)ACV encapsulated in erythrocytes provides effective protection against HSV-1 replication in human macrophages and also partially against the HSV-1 thymidine kinase-deficient strain. Thus, ACVp(2)ACV acts as an effective antiviral prodrug against HSV-1.
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PMID:A new homodimer of aciclovir as a prodrug with increased solubility and antiviral activity. 1939 1

Bicyclic aryl furano pyrimidines represent the most potent anti-varicella zoster virus (VZV) agents reported to date. Lead compounds have 50% effective concentration (EC(50)) values in vitro that are in the subnanomolar range and selectivity index values that exceed 1 million. They have an absolute requirement for VZV thymidine kinase and most likely act as their phosphate forms. Some structural modification (such as aryl substitution in the base moiety) is tolerated, whereas little sugar modification is acceptable. The Cf1743 compound has proved to be significantly more potent than all reference anti-VZV compounds, as measured either by inhibition of infectious virus particles and/or viral DNA production; however, the high lipophilicity and very low water solubility of this compound gives poor oral bioavailability (<14%). Use of the modified cyclodextrin captisol and the synthesis of the 5'-monophosphate prodrug of Cf1743 has significantly improved water solubility, but does not give any enhancement in oral bioavailability. By contrast, the synthesis of the ether series does not give any further improvement in terms of solubility. The most promising prodrug to emerge to date is the hydrochloric salt of the 5'-valyl-ester, designated as FV-100. Its uptake into cells has been studied using fluorescent microscopy and biological assays, which have indicated that the compound is efficiently taken up by the cells after a short period of incubation.
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PMID:FV-100: the most potent and selective anti-varicella zoster virus agent reported to date. 2005 98

Drinking water must be disinfected prior to its distribution for human consumption. This water treatment process generates disinfection by-products (DBPs), formed by the interaction of the disinfectant with organic matter, anthropogenic contaminants and inorganic (bromide/iodide) matter naturally present in source water. Due to the potential genotoxic/carcinogenic risk of these DBPs, we have investigated the mutagenic potential of six of such compounds on the thymidine kinase (Tk) gene in the well-validated mouse lymphoma assay (MLA). The MLA quantifies a wide range of genetic alterations affecting the expression of this gene in L5178Y/Tk(+/-)-3.7.2C cells. In this study we selected six emerging DBPs, corresponding to three different chemical classes: halonitromethanes (bromonitromethane and trichloronitromethane), halogenated acetaldehydes (tribromoacetaldehyde and chloral hydrate) and hydroxyfuranones (mucobromic and mucochloric acids), each class including one chlorinated and one brominated form. The results showed that after 4h of treatment, only mucobromic acid increased the frequency of mutant colonies, with a higher proportion of small colonies, which would indicate a clastogenic potential. This is the first study reporting mutagenicity data in mammalian cells for the six selected DBPs.
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PMID:Mutagenic analysis of six disinfection by-products in the Tk gene of mouse lymphoma cells. 2156 8


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