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1.
Chemosphere ; 239: 124666, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31479911

RESUMO

The toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) is well known, and for this reason studying and monitoring these chemicals is fundamental. Activated carbon fibers (ACFs) are made of an adsorbent material widely used in the industrial field for the removal of micropollutants. The first step in this work was to perform a physico-chemical characterization of the adsorbent, focused on the analytical use of it. In particular, its specific surface area was defined around 2500 m2/g consisting in a homogeneous microporosity distribution and the characterization of ACF surface functional groups pointed out a balance between basic and acidic group. The validity of using the ACF as solid phase extraction and as passive sampler for PCDD/Fs and PCBs in water, has been evaluated by the percentage recovery (R %) of 13C12-labeled standards of PCDD/Fs and PCBs added in a known volume of water. The results were compared to the R% of Liquid-Liquid Extraction which showed a better reproducibility of the results and the proposed method satisfy completely the requirements of US EPA reference methods.


Assuntos
Carvão Vegetal/química , Dibenzofuranos Policlorados/análise , Monitoramento Ambiental/métodos , Recuperação e Remediação Ambiental/métodos , Bifenilos Policlorados/análise , Dibenzodioxinas Policloradas/análise , Benzofuranos/análise , Fibra de Carbono , Reprodutibilidade dos Testes , Extração em Fase Sólida , Água
2.
ACS Med Chem Lett ; 10(4): 487-492, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30996784

RESUMO

The value of including protein flexibility in structure-based drug design (SBDD) is widely documented, and currently, molecular dynamics (MD) simulations represent a powerful tool to investigate protein dynamics. Yet, the inclusion of MD-derived information in pre-existing SBDD workflows is still far from trivial. We recently published an integrated MD-FLAP (Fingerprints for Ligands and Proteins) approach combining MD, clustering and Linear Discriminant Analysis (LDA) for enhancing accuracy, efficacy, and for protein conformational selection in virtual screening (VS) campaigns. Here we prospectively applied the MD-FLAP workflow to discover novel chemotypes inhibiting the Casein Kinase 1 delta (CSNK1D) enzyme. We first obtained a VS model able to separate active from inactive compounds, with a global AUC of 0.9 and a partial ROC enrichment at 0.5% of 0.18, and use it to mine the internal Pfizer screening database. Seven active molecules sharing a phenyl-indazole scaffold, not yet reported among CSNK1D inhibitors, were found. The most potent inhibitor showed an IC50 of 134 nM.

3.
Environ Sci Pollut Res Int ; 26(16): 16781-16799, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30997642

RESUMO

Despite the Mediterranean Sea basin is among the most sensitive areas over the world for climate change and air quality issues, it still remains less studied than the oceanic regions. The domain investigated by the research ship Minerva Uno cruise in Summer 2015 was the Tyrrhenian Sea. An overview on the marine boundary layer (MBL) concentration levels of carbonyl compounds, ozone (O3), and sulfur dioxide (SO2) is reported. The north-western Tyrrhenian Sea samples showed a statistically significant difference in acetone and SO2 concentrations when compared to the south-eastern ones. Acetone and SO2 values were higher in the southern part of the basin; presumably, a blend of natural (including volcanism) and anthropogenic (shipping) sources caused this difference. The mean acetone concentration reached 5.4 µg/m3; formaldehyde and acetaldehyde means were equal to 1.1 µg/m3 and 0.38 µg/m3, respectively. Maximums of 3.0 µg/m3 for formaldehyde and 1.0 µg/m3 for acetaldehyde were detected along the route from Civitavecchia to Fiumicino. These two compounds were also present at levels above the average in proximity of petrol-refining plants on the coast; in fact, formaldehyde reached 1.56 µg/m3 and 1.60 µg/m3, respectively, near Milazzo and Augusta harbors; meanwhile, acetaldehyde was as high as 0.75 µg/m3 at both sites. The levels of formaldehyde agreed with previously reported measurements over Mediterranean Sea and elsewhere; besides, a day/night trend was observed, confirming the importance of photochemical formation for this pollutant. According to this study, Mediterranean Sea basin, which is a closed sea, was confirmed to suffer a high anthropic pressure impacting with diffuse emissions, while natural contribution to pollution could come from volcanic activity, particularly in the south-eastern Tyrrhenian Sea region.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Oxigênio/química , Compostos Orgânicos Voláteis/análise , Itália , Mar Mediterrâneo , Ozônio/análise , Processos Fotoquímicos , Estações do Ano , Dióxido de Enxofre/análise
4.
J Comput Aided Mol Des ; 33(2): 295-305, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30603820

RESUMO

The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contain antimicrobial resistance are urgently needed. Class A carbapenemases include members of the KPC, GES and SFC families. These enzymes have the ability to hydrolyse penicillins, cephalosporins and carbapenems, while also being less susceptible to available beta-lactam inhibitors, such as clavulanic acid. The KPC family is the most prevalent. It is mostly found on plasmids in Klebsiella pneumoniae, meaning that great amounts of attention, in terms of inhibitor design and structural biology, have been dedicated to it, whereas no efforts have yet been dedicated to GES-type enzymes, despite their ability to rapidly and horizontally disseminate. We herein report the first in silico screening against GES-5, which is the most dangerous GES-type beta-lactamase, using a library of 800K commercially available candidates that all share drug-like properties, such as their MW, logP, rotatable bonds and HBA/HBD atoms. The best screening results were filtered to enrich the number of different chemotypes, and then submitted to molecular docking. The 34 most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5. Six hits acted as inhibitors, in the high micromolar range, towards GES-5 and led to the identification of the first, novel chemotypes with inhibitory activity against this clinically relevant carbapenemase.

5.
J Biomol Struct Dyn ; 37(2): 291-306, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29334320

RESUMO

Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine, thereby enhancing and compensating a loss of dopaminergic neurotransmission, and to exert neuroprotective response because of their accumulation in the cytoplasm, are required. By means of homology modeling, molecular docking, and molecular dynamics simulations, we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations, critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake, through in vitro live cell imaging experiments. Taken together, our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Inibidores da Captação de Dopamina/química , Dopamina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Sequência de Aminoácidos , Sítios de Ligação , Técnicas de Cultura de Células , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Descoberta de Drogas , Humanos , Ligações de Hidrogênio , Ligantes , Modelos Moleculares , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Especificidade por Substrato
6.
J Med Chem ; 61(1): 360-371, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29240409

RESUMO

Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that has raised great interest in recent years, since its contribution in xenobiotic metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack. Therefore, novel strategies to predict the potential liability of new entities toward the AOX enzyme are urgently needed to increase effectiveness, reduce costs, and prioritize experimental studies. In the present work, we present the most up-to-date computational method to predict liability toward human AOX (hAOX), for applications in drug design and pharmacokinetic optimization. The method was developed using a large data set of homogeneous experimental data, which is also disclosed as Supporting Information .


Assuntos
Aldeído Oxidase/metabolismo , Modelos Moleculares , Aldeído Oxidase/química , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Especificidade por Substrato
7.
J Sep Sci ; 40(17): 3469-3478, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28703493

RESUMO

The European and American methods for the determination of polychlorodibenzo-p-dioxins and polychlorodibenzofurans in stationary source emissions require a high-resolution mass spectrometer detector. At the same time, all of the 17 toxic 2,3,7,8-chlorine-substituted isomers have to be separated by an appropriate chromatographic method. The resulting analysis has long runtimes and sometimes a double-column run is needed, which results in a huge waste of time, money and manual labor. To obtain a fast and cost-effective but still reliable analytical system, a single-column gas chromatography with hydrogen as carrier gas and tandem mass spectrometry detection is proposed. The use of hydrogen as the carrier gas is a good choice to shorten runtimes and improve the chromatographic resolution, while tandem mass spectrometry is a well-known alternative for this analysis. All the chromatographic and mass spectrometric parameters fill the requirements of the reference methods with a 35% reduction of runtimes. The accuracy is tested with three fly ash samples of a proficiency interlaboratory test. A good correlation between the results is obtained (R2  = 0.992, slope = 0.9675), and no coelutions are noted. The system robustness is tested during 5 years of constant use and the maximal relative standard deviation of the relative response factor is 18.8%.

8.
J Chem Inf Model ; 55(10): 2256-74, 2015 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-26355717

RESUMO

The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of nanoseconds of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite ( http://www.bikitech.com [accessed July 21, 2015]). Then, instead of applying arbitrary selection criteria, that is, RMSD, pharmacophore properties, or enrichment performances, we allowed the linear discriminant analysis algorithm implemented in FLAP ( http://www.moldiscovery.com [accessed July 21, 2015]) to automatically choose the best performing conformational states among medoids and X-ray structures. Retrospective virtual screenings confirmed that ensemble receptor protocols outperform single rigid receptor approaches, proved that computationally generated conformations comprise the same quantity/quality of information included in X-ray structures, and pointed to the MD-FLAP approach as a valuable tool for improving VS performances.


Assuntos
Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Dinâmica Molecular , Proteínas/química , Sítios de Ligação , Bases de Dados como Assunto , Ligantes , Estrutura Molecular , Ligação Proteica
9.
J Air Waste Manag Assoc ; 64(11): 1270-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25509548

RESUMO

Nitrous oxide (N2O) is the third most important greenhouse gas after carbon dioxide and methane, and contributes about 6% to the greenhouse effect. Nitrous oxide is a minor component of the atmosphere, and it is a thousand times less than carbon dioxide (CO2). Nevertheless, it is much more potent than CO2 and methane, owing to its long stay in the atmosphere of approximately 120 yr and the high global warmingpotential (GWP) of298 times that of CO2. Although greenhouse gases are natural in the atmosphere, human activities have changed the atmospheric concentrations. Most of the values of emission of nitrous oxide are still obtained by means ofemission factors and not actually measured; the lack ofreal data may result in an underestimation ofcurrent emissions. The emission factors used for the calculation of N2O can be obtained from the "Guidelines for the implementation of the national inventory of emissions" of the Intergovernmental Panel on Climate Change, which refer to all nations for the realization of their inventory. This study will present real data, measured in several Italian cement plants with different characteristics. The work also shows a comparison between N2O concentration measured with in situ-Fourier transform IR (FTIR) and the reference method EN ISO 21258 based on nondispersive IR (NDIR), in order to investigate the interfering compounds in the measurement with NDIR.


Assuntos
Poluentes Atmosféricos/química , Materiais de Construção , Monitoramento Ambiental/métodos , Indústrias , Espectrofotometria Infravermelho/métodos , Análise de Fourier , Óxido Nitroso
10.
ChemMedChem ; 9(7): 1501-11, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24616267

RESUMO

Cystalysin from Treponema denticola is a pyridoxal 5'-phosphate dependent lyase that catalyzes the formation of pyruvate, ammonia, and sulfide from cysteine. It is a virulence factor in adult periodontitis because its reaction contributes to hemolysis, which sustains the pathogen. Therefore, it was proposed as a potential antimicrobial target. To identify specific inhibitors by structure-based in silico methods, we first validated the crystal structure of cystalysin as a reliable starting point for the design of ligands. By using single-crystal absorption microspectrophotometry, we found that the enzyme in the crystalline state, with respect to that in solution, exhibits: 1) the same absorption spectra for the catalytic intermediates, 2) a close pKa value for the residue controlling the keto enamine ionization, and 3) similar reactivity with glycine, L-serine, L-methionine, and the nonspecific irreversible inhibitor aminoethoxyvinylglycine. Next, we screened in silico a library of 9357 compounds with the Fingerprints for Ligands and Proteins (FLAP) software, by using the three-dimensional structure of cystalysin as a template. From the library, 17 compounds were selected and experimentally evaluated by enzyme assays and spectroscopic methods. Two compounds were found to competitively inhibit recombinant T. denticola cystalysin, with inhibition constant (Ki ) values of 25 and 37 µM. One of them exhibited a minimum inhibitory concentration (MIC) value of 64 µg mL(-1) on Moraxella catarrhalis ATCC 23246, which proves its ability to cross bacterial membranes.


Assuntos
Cistationina gama-Liase/antagonistas & inibidores , Inibidores Enzimáticos/química , Treponema denticola/enzimologia , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Domínio Catalítico , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Periodontite/tratamento farmacológico , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Treponema denticola/efeitos dos fármacos
11.
Food Chem ; 151: 374-8, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24423546

RESUMO

The importance of free fatty acids (FFAs) in wort has been known for a long time because of their influence on beer quality and yeast metabolism. Lipids have a beneficial effect on yeast growth during fermentation as well as negative effects on beer quality. Lipids content of beer affects the ability to form a stable head of foam and plays an important role in beer staling. Moreover, the ratio of unsaturated and saturated fatty acids seems to be related to gushing problems. A novel, simple, and reliable procedure for quantitative analysis of FFAs in wort was developed and validated. The determination of FFAs in wort was achieved via liquid-liquid cartridge extraction, purification of FFA fraction by solid phase extraction, boron trifluoride in methanol methylation, and injection into GC-FID system. The proposed method has high accuracy (<0.3%, expressed as the bias), high precision (<1.2%, RSD), and recoveries ranging from 74% to 98%. The method was tested on two different wort samples (9° and 12° Plato).


Assuntos
Cerveja/análise , Ácidos Graxos não Esterificados/química , Lipídeos/análise , Extração Líquido-Líquido/métodos , Extração em Fase Sólida/métodos , Fermentação
12.
PLoS One ; 8(10): e77558, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24167577

RESUMO

The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lack O-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two isozymes via a ligand- and structure-based in silico screening of a subset of the ZINC library using FLAP. The binding affinities of the most promising candidates were measured in vitro on purified O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B from Salmonella typhimurium by a direct method that exploits the change in the cofactor fluorescence. Two molecules were identified with dissociation constants of 3.7 and 33 µM for O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, respectively. Because GRID analysis of the two isoenzymes indicates the presence of a few common pharmacophoric features, cross binding titrations were carried out. It was found that the best binder for O-acetylserine sulfhydrylase-B exhibits a dissociation constant of 29 µM for O-acetylserine sulfhydrylase-A, thus displaying a limited selectivity, whereas the best binder for O-acetylserine sulfhydrylase-A exhibits a dissociation constant of 50 µM for O-acetylserine sulfhydrylase-B and is thus 8-fold selective towards the former isozyme. Therefore, isoform-specific and isoform-independent ligands allow to either selectively target the isozyme that predominantly supports bacteria during infection and long-term survival or to completely block bacterial cysteine biosynthesis.


Assuntos
Antibacterianos , Bactérias , Proteínas de Bactérias/antagonistas & inibidores , Cisteína Sintase/antagonistas & inibidores , Inibidores Enzimáticos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/enzimologia , Bactérias/crescimento & desenvolvimento , Proteínas de Bactérias/metabolismo , Cisteína/biossíntese , Cisteína Sintase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo
13.
Drug Discov Today Technol ; 10(1): e155-65, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24050245

RESUMO

Chemical modifications of drugs induced by phase I biotransformations significantly affect their pharmacokinetic properties. Because the metabolites produced can themselves have a pharmacological effect and an intrinsic toxicity, medicinal chemists need to accurately predict the sites of metabolism (SoM) of drugs as early as possible. However, site of metabolism prediction is rarely accompanied by a prediction of the relative abundance of the various metabolites. Such a prediction would be a great help in the study of drug­ drug interactions and in the process of reducing the toxicity of potential drug candidates. The aim of this paper is to present recent developments in the prediction of xenobiotic metabolism and to use concrete examples to explain the computational mechanism employed.


Assuntos
Algoritmos , Sistema Enzimático do Citocromo P-450/metabolismo , Preparações Farmacêuticas/metabolismo , Software , Simulação por Computador , Humanos
14.
Infection ; 41(2): 409-14, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23001543

RESUMO

PURPOSE: Extrapulmonary tuberculosis (EPTB) is frequently seen in human immunodeficiency virus (HIV)-infected individuals in Sub-Saharan Africa and recent work has shown point-of-care (POC) ultrasound to be a diagnostic aid in the resource-limited, highly endemic setting. Its role in industrialized countries, however, has rarely been studied. With international migration, EPTB is increasingly seen in European hospitals. This study reports ultrasound findings and discusses the diagnostic relevance of EPTB in an industrialized country setting. METHODS: In this retrospective study, we describe a cohort of 27 patients with a predominantly immigrant background diagnosed with HIV and EPTB in Northern Italy and evaluate the role of ultrasound in their clinical management. All inpatient files of HIV-positive individuals admitted to our hospital with culture-proven diagnosis of EPTB were reviewed, along with chest X-rays and ultrasound studies. The outcome and results of long-term follow-up were extracted. RESULTS: A total of 243 HIV-positive inpatients were identified between January 2005 and November 2011. Twenty-seven of the patients [11.1 %, 95 % confidence interval (CI) 7.4-15.7] were diagnosed with EPTB. Ultrasound showed a typical pattern of enlarged abdominal lymph nodes and focal lesions in the spleen and liver in 22 patients (81.5 %, 95 % CI 7.4-15.7) and, thus, helped to raise the suspicion of mycobacterial infection. CONCLUSION: As disseminated mycobacterial infections in HIV-positive patients can be treated effectively if diagnosed early, and typical sonographic findings are seen in the majority of these patients, we suggest that POC ultrasound should be integrated in diagnostic and screening algorithms for EPTB in developed countries.


Assuntos
Soropositividade para HIV/microbiologia , Tuberculose/diagnóstico por imagem , Adulto , Técnicas Bacteriológicas , Coinfecção/microbiologia , Coinfecção/virologia , Intervalos de Confiança , Emigrantes e Imigrantes , Feminino , Febre/microbiologia , Febre/patologia , Febre/virologia , Seguimentos , Soropositividade para HIV/epidemiologia , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Baço/patologia , Tórax/diagnóstico por imagem , Tórax/microbiologia , Resultado do Tratamento , Tuberculose/epidemiologia , Ultrassonografia , Adulto Jovem
15.
J Med Chem ; 55(22): 10272-6, 2012 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-23075414

RESUMO

Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 µM and activity against ovarian cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits anticancer activity against ovarian cancer cells.


Assuntos
Acetanilidas/farmacologia , Ensaios de Triagem em Larga Escala , Neoplasias Ovarianas/tratamento farmacológico , Tiazóis/química , Timidilato Sintase/antagonistas & inibidores , Acetanilidas/síntese química , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Estrutura Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Timidilato Sintase/metabolismo , Células Tumorais Cultivadas
16.
Case Rep Med ; 2011: 202083, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21541220

RESUMO

We describe a fatal case of imported malaria where the sole finding revealed at the postmortem evaluation was an acute lymphocytic myocarditis with myocardiolysis. This case recalls the potential importance of myocardial injury in the prognosis of malaria and prompts a reevaluation of current perspectives on the pathogenesis of severe falciparum infection. In the light of this, we have reviewed the cases of cardiac complications in malaria published to date.

17.
J Chem Inf Model ; 50(8): 1442-50, 2010 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-20690627

RESUMO

The performance of FLAP (Fingerprints for Ligands and Proteins) in virtual screening is assessed using a subset of the DUD (Directory of Useful Decoys) benchmarking data set containing 13 targets each with more than 15 different chemotype classes. A variety of ligand and receptor-based virtual screening approaches are examined, using combinations of individual templates 2D structures of known actives, a cocrystallized ligand, a receptor structure, or a cocrystallized ligand-biased receptor structure. We examine several data fusion approaches to combine the results of the individual virtual screens. In doing so, we show that excellent chemotype enrichment is achieved in both single target ligand-based and receptor-based approaches, of approximately 17-fold over random on average at a false positive rate of 1%. We also show that using as much starting knowledge as possible improves chemotype enrichment, and that data fusion using Pareto ranking is an effective method to do this giving up to 50% improvement in enrichment over the single methods. Finally we show that if inactivity or decoy data is incorporated, automatically training the scoring function in FLAP improves recovery still further, with almost 2-fold improvement over the enrichments shown by the single methods. The results clearly demonstrate the utility of FLAP for virtual screening when either a limited or wide range of prior knowledge is available.


Assuntos
Desenho de Drogas , Proteínas/metabolismo , Bases de Dados de Proteínas , Ligantes , Modelos Moleculares , Ligação Proteica
18.
J Med Microbiol ; 58(Pt 12): 1652-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19713361

RESUMO

A case is reported of cerebellar abscess and diffuse cerebritis due to Gemella morbillorum. The clinical course was 'biphasic', developing with an acute meningeal infection followed shortly afterwards by suppuration in the cerebellar and cerebral parenchyma; this pattern seemed to suggest a latent survival of the aetiological agent, probably within the central nervous system (CNS), despite systemic antibiotic therapy. Based upon a review of cases so far described, infections of the CNS caused by G. morbillorum appear to be an emerging reality.


Assuntos
Infecções por Bactérias Gram-Positivas/microbiologia , Meningites Bacterianas/microbiologia , Staphylococcaceae/isolamento & purificação , Idoso , Antibacterianos/uso terapêutico , Abscesso Encefálico/microbiologia , Abscesso Encefálico/patologia , Evolução Fatal , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Masculino , Meningites Bacterianas/tratamento farmacológico
19.
J Med Microbiol ; 57(Pt 7): 904-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18566153

RESUMO

A case is reported of Staphylococcus caprae meningitis due to infection of an intraspinal analgesia pump. The subclinical and pauci-symptomatic clinical course of the infection strongly suggested a chronic device contamination.


Assuntos
Bombas de Infusão Implantáveis/efeitos adversos , Injeções Espinhais/métodos , Meningites Bacterianas/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus/isolamento & purificação , Analgésicos/administração & dosagem , Líquido Cefalorraquidiano/microbiologia , Feminino , Humanos , Pessoa de Meia-Idade , Staphylococcus/classificação
20.
J Infect ; 53(4): 266-73, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16388852

RESUMO

Fatality rates and prognostic factors for mortality due to Enterococcus spp. bacteraemia have not yet been fully defined in the setting of neutropenic patients affected with haematological malignancies. We have performed a retrospective, multi-centre cohort study on 98 episodes of Enterococcus bacteraemia occurring in patients hospitalised from January 1984 to December 2001 at the oncohaematology units in two tertiary-care hospitals (Verona Hospital and Vicenza Hospital, in north-east Italy). E. faecalis was isolated in 52 cases (53%), E. faecium in 39 (39.8%), E. avium in four, E. durans in one, and untyped Enterococcus spp. in two other cases; vancomycin resistance was detected in 15 (15.3%) isolates. A global mortality rate of 41.8% (41/98 cases) was revealed; Enterococcus spp. bacteraemia was associated with a fatal outcome in 29/98 cases (29.5%). The following variables were independently associated with an increased risk of death by multivariate analysis of survival: age > or =50 years (OR 3.74; 95% CI 1.35-10.32), pneumonia (OR 4.70; 95% CI 1.67-13.20), and shock (OR 13.7; 95% CI 1.23-152.43), while the initial phase of haematological disease (responsive to chemotherapy) appeared to be protective (OR 0.23; 95% CI 0.008-0.64, P level 0.005); however, pneumonia alone (OR 7.2, 95% CI 2.52-20.88) was independently associated with fatal outcome by multivariate analysis for death related to enterococcal bacteraemia. In our experience, the poor outcome proper to enterococcal bacteraemia appears to be directly related to underlying disease, patient's age, presence of pneumonia and shock; in contrast, severe neutropaenia, antibiotic resistance, and species of Enterococcus do not appear to affect the fatality rate significantly.


Assuntos
Bacteriemia/mortalidade , Infecções por Bactérias Gram-Positivas/mortalidade , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Neutropenia/mortalidade , Adolescente , Adulto , Idoso , Bacteriemia/microbiologia , Estudos de Coortes , Enterococcus/classificação , Enterococcus/isolamento & purificação , Feminino , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Fatores de Risco
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