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This article has been retracted.
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Pollutants in real aquatic systems commonly occur as chemical mixtures. Yet, the corresponding risk assessment is still mostly based on information on single-pollutant toxicity, accepting the assumption that pollutant mixtures exhibit additive toxicity effect which is often not the case. Therefore, it is still better to use the experimental approach. Unfortunately, experimental determination of toxicity for each mixture is practically unfeasible. In this study, quantitative structure-activity relationship (QSAR) models for the prediction of toxicity of binary mixtures towards bioluminescent bacteria Vibrio fischeri were developed at three toxicity levels (EC10, EC30 and EC50). For model development, experimentally determined toxicity values of 14 pollutants (pharmaceuticals and pesticides) were correlated with their structural features, applying multiple linear regression together with genetic algorithm. Statistical analysis, internal validation and external validation of the models were carried out. The toxicity is accurately predicted by all three models. EC30 and EC50 values are mostly influenced by geometrical distances between nitrogen and sulfur atoms. Furthermore, the simultaneous presence of oxygen and chlorine atoms in mixture can induce the increase in toxicity. At lower effect levels (EC10), nitrogen atom bonded to different groups has the highest impact on mixture toxicity. Thus, the analysis of the descriptors involved in the developed models can give insight into toxic mechanisms of the binary systems.
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Praguicidas , Preparações Farmacêuticas , Poluentes Químicos da Água , Aliivibrio fischeri , Praguicidas/toxicidade , Relação Quantitativa Estrutura-Atividade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
In a laboratory model system consisting of fly ash from municipal waste incinerator, CuCl2 x 2H2O, NaCl and activated carbon in N2 + 10% O2 atmosphere, the de novo synthetic reactions of formation of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) were studied under laboratory conditions in the presence of sulfur dioxide, hydrogen peroxide, and sulfuric acid. It has been found that the formation of PCDD is suppressed by sulfur dioxide more efficiently than the formation of PCDF. A similar effect has also been observed in the presence of hydrogen peroxide. The formation of PCDF is strongly suppressed in the presence of sulfuric acid. On the basis of the experimental results and thermodynamic calculations, the following mechanisms are proposed and discussed: oxidative destruction of PCDD and PCDF oxygen rings, conversion of cupric chloride and possibly also cupric oxide into the non-reactive sulfate, and the Deacon oxychlorination processes catalyzed by cupric chloride.
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Peróxido de Hidrogênio/química , Bifenilos Policlorados/síntese química , Dibenzodioxinas Policloradas/análogos & derivados , Dióxido de Enxofre/química , Ácidos Sulfúricos/química , Carbono/química , Cinza de Carvão , Cobre/química , Laboratórios , Modelos Químicos , Material Particulado/química , Bifenilos Policlorados/química , Dibenzodioxinas Policloradas/síntese química , Dibenzodioxinas Policloradas/química , Cloreto de Sódio/química , Termodinâmica , Água/químicaRESUMO
The authors describe their experiences with the therapy of CVI and inform about the present state of the surgical knowledge about this topic. The classification is based on the last recommendations from Roma (2000, modified CEAP). The surgical therapy of CVI they've divided into surgery of superficial venous system, surgical therapy of perforators and possibilities of surgical approach in the therapy of deep veins pathology (reflux and obstruction). They emphasize complex therapy in case of each patient and recommend the use of compressive and medical therapy as permanent and all life lasting method as the best strategy in this group of patients.
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Insuficiência Venosa/cirurgia , Doença Crônica , Humanos , Insuficiência Venosa/classificação , Insuficiência Venosa/diagnóstico , Insuficiência Venosa/prevenção & controleRESUMO
A statistical analysis of NMR-derived binding data on 11 protein targets was performed to identify molecular motifs that are preferred for protein binding. The analysis indicates that compounds which contain a biphenyl substructure preferentially bind to a wide range of proteins and that high levels of specificity (>250-fold) can be achieved even for these small molecules. These results suggest that high-throughput screening libraries that are enriched with biphenyl-containing compounds can be expected to have increased chances of yielding high-affinity ligands for proteins, and they suggest that the biphenyl can be utilized as a template for the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets.
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Compostos de Bifenilo/química , Proteínas/química , Bases de Dados Factuais , Ligantes , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Molecular diversity, combinatorial chemistry and automated synthesis are helping usher in a new age in medicinal chemistry. The tools and practices of computational chemistry and molecular modeling are rising to the challenges and opportunities presented by the current trends in drug discovery and design. Recent advances include a number of new and meaningful measures of molecular diversity and the use of genetic algorithms to help design diverse libraries.
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Química Orgânica/métodos , Algoritmos , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Reprodutibilidade dos Testes , SoftwareRESUMO
Ofloxacin, a potent quinolone antibacterial agent, has a tricyclic ring structure with a methyl group attached to the asymmetric carbon at the C-3 position on the oxazine ring. The S isomer (DR-3355) of ofloxacin has antibacterial activity up to 2 orders of magnitude greater than that of the R isomer (DR-3354). This differential antibacterial activity was not due to different drug transport mechanisms of the two isomers but was found to be derived from the inhibitory activity against the target enzyme, DNA gyrase. Previous mechanistic studies have suggested that the bactericidal effect of the drug is mediated through the stabilization of a cleavable complex via a cooperative drug binding process to a partially denatured DNA pocket created by DNA gyrase. The drug binds to supercoiled DNA in a manner similar to that to which it binds to the enzyme-DNA complex. In the present studies, we first examined the binding of the two radiolabeled ofloxacin enantiomers to supercoiled pUC9 plasmid DNA. Surprisingly, the two enantiomers possessed similar apparent binding affinities and binding cooperatives. The major difference in binding between the two stereoisomers was the molar binding ratio: 4 for the more active S isomer versus 2 for the less active R isomer. We next examined the relative binding potencies of the stereoisomers to the DNA-DNA gyrase complex. The results of a competition assay showed that (S)-ofloxacin binds 12-fold better to the complex than (R)-ofloxacin. The binding potencies of the two enantiomers and two other quinolones correlated well with their respective concentrations causing 50% inhibition against DNA gyrase. The results are interpreted by a stacking model by using the concept of the cooperative drug-DNA binding mechanism, indicating that the potencies of quinolones cannot be determined solely by the DNA binding affinity and cooperativity but can also be determined by their capability in maximally saturating the binding site. The capability of the drug in saturating the binding pocket manifests itself in an increased efficacy at inhibiting the enzyme through a direct interaction between the drug and the enzyme. The results augment the previous suggestion that the binding pocket in the enzyme-DNA complex involves multiple receptor groups including not only DNA bases but also a gyrase subunit. The higher level of potency of (S)-ofloxacin is proposed to derive from the fact that a greater number of molecules are assembled in the pocket. This greater number of molecules optimizes the interaction between the drug and the enzyme, possibly through a contact between the C-7 substituent and the quinolone pocket on the B subunit of DNA gyrase.
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Anti-Infecciosos/farmacologia , Escherichia coli/efeitos dos fármacos , Ofloxacino/farmacologia , Inibidores da Topoisomerase II , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Simulação por Computador , DNA Topoisomerases Tipo II/metabolismo , DNA Bacteriano/metabolismo , DNA Super-Helicoidal/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Testes de Sensibilidade Microbiana , Modelos Químicos , Modelos Moleculares , Ofloxacino/química , Ofloxacino/metabolismo , Plasmídeos , EstereoisomerismoRESUMO
(2RS,4R)-3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
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Permeabilidade Capilar/efeitos dos fármacos , Edema/tratamento farmacológico , Indóis/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Tiazóis/farmacologia , Administração Oral , Animais , Edema/induzido quimicamente , Técnicas In Vitro , Indóis/síntese química , Indóis/química , Indóis/uso terapêutico , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley , Serotonina/sangue , Pele/efeitos dos fármacos , Pele/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/uso terapêuticoRESUMO
In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optimize all low-energy conformations by any suitable method. For each conformation we then use ALADDIN to calculate the location of points to be considered as part of the superposition. These points include atoms in the molecule and projections from the molecule to hydrogen-bond donors and acceptors or charged groups in the binding site. These positions and the relative energy of each conformation are the input to our new program DISCO. It uses a clique-detection method to find superpositions that contain at least one conformation of each molecule and user-specified numbers of point types and chirality. DISCO is fast; for example, it takes about 1 min CPU to propose pharmacophores from 21 conformations of seven molecules. We typically run DISCO several times to compare alternative pharmacophore maps. For D2 dopamine agonists DISCO shows that the newer 2-aminothiazoles fit the traditional pharmacophore. Using site points correctly identifies the bioactive enantiomers of indoles to compare with catechols whereas using only ligand points leads to selecting the inactive enantiomer for the pharmacophore map. In addition, DISCO reproduces pharmacophore maps of benzodiazepines in the literature and proposes subtle improvements. Our experience suggests that clique-detection methods will find many applications in computational chemistry and computer-assisted molecular design.
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Benzodiazepinas/química , Dopaminérgicos/química , Modelos Moleculares , Algoritmos , Sítios de Ligação , Conformação Molecular , Estrutura Molecular , Software , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide N-1-naphthylphthalamic acid (NPA). A 3D model was derived from critical features of a set of ligands for the NPA receptor, a suggested binding conformation is proposed, and implications for the topographical features of the NPA receptor are discussed. This model, along with 3D structural analysis techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the criteria of the model, 77 representative molecules were evaluated for their ability to compete for the binding of [3H]NPA to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, representing chemical classes not included in the original compound set, were also found to inhibit polar auxin transport through corn coleoptile sections. Thus, this study demonstrates that 3D analysis techniques can identify active, novel ligands for biochemical target sites with concomitant physiological activity.