Inovação do método MIA-QSAR: aplicação para doenças tropicais negligenciadas

Multivariate image analysis applied to the quantitative structure-activity relationships (MIA-QSAR) is a 2D QSAR technique that has been presenting promising outcomes for the development of new drug candidates, due to its simplicity, rapidity and low cost. In this way, the present study aims at introducing, consolidating and improving the new dimensions named aug-MIA-QSAR and aug-MIA-QSARcolor, as well as applying them to the study of neglected diseases, in order to obtain new drug targets using chemico-biological interpretation of the MIA molecular descriptors. Four compound data sets with experimental bioactivities against Chagas disease, malaria, dengue and schistosomiasis were evaluated using three approaches: MIA-QSARt, aug-MIA-QSAR and aug-MIA-QSARcolor. In general, representations of atoms as spheres with different colors and sizes proportional to the corresponding van der Waals radii (aug-MIA approaches) improved the predictive ability and interpretability in all data sets. The use of colors proportional to the Pauling´s electronegativity showed that MIA descriptors are capable of identifying periodic properties relevant for the studied activity. Finally, solid colors instead of spotlighted atoms allowed a correct identification of atoms by means of pixel values in the studies for malaria, dengue and schistosomiasis, which were, subsequently, useful for the chemical interpretation related to the bioactivity. It can be inferred that semicarbazones and thiosemicarbazones derivative with a tri-substituted ring in R1 group and a trifluoro methyl group in the R 3 position instead of a chlorine antitripanossoma resulted in higher activity. The antimalarial activity of quinolon-4(1H)imines can be improved if: 1) R1 and R2 are electron donor groups, 2) R3 has long aminoalkyl chains, and 3) R4 possesses substituents with big atomic volume. In the study for dengue, it was found that tetrapeptides with unbranched small size amino acids in the A1 and A4 positions can increase the substrate affinity (Km) to the NS3 protein, and when in A1 and A2 positions, the substrate cleavage rate (kcat). On the other hand, acidic amino acids in the A2 and A4 positions were found to be related with low substrate affinity to the NS3 protein and when present in A1, with low substrate cleavage rate. Finally, the presence of metoxy substituents in R1 (or R2) and R5 in the neolignan backbone can favor their antischistosomal activity.

Pesquisa de atividade antitumoral e mutagênica in vitro de produtos naturais

Pós-graduação em Ciências Farmacêuticas - FCFAR

Estrutura e função de mastoparanos dos venenos de vespas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Apocinina e metóxi-catecóis correlatos: relação entre estrutura molecular e inibição da ativação do complexo NADPH oxidase

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Estudos estruturais com miotoxinas do tipo fosfolipases A2 homólogas do veneno de serpentes do gênero Bothrops: avanços no entendimento da relação estrutura-função

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estudo do potencial antimutagênico, mutagênico, estrogênico e antibacteriano de flavonoides

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Planejamento de novos derivados da Edaravona

Um estudo teórico detalhado da edaravona foi realizado usando o método TFD (Teoria do Funcional da Densidade) com o conjunto de base B3LYP/6-31G*, com o objetivo de esclarecer o mecanismo sequestraste de radical e a influência do tautomerismo da edaravona em condições ácidas, importantes para auxiliar na elucidação do mecanismo de sequestro de radical pela edaravona no processo isquêmico. Em estudos teóricos anteriores, a tautomerização, o efeito do solvente e a abstração do elétron não foram considerados. Em nosso estudo, a estabilidade e reatividade foram determinadas através de parâmetros geométricos e energéticos. Os cálculos foram realizados em fase gasosa e o método PCM em fase aquosa e metanólica. As condições ácidas ou básicas foram consideradas pelas energias de dissociação e protonação, com consequente formação das formas aniônicas e catiônicas, respectivamente. As propriedades antioxidantes foram calculadas com base nos valores de HOMO, potencial de ionização (PI) e energia de dissociação da ligação (EDL). Os valores de HOMO e PI mostraram que o tautomero N-H é melhor antioxidante pela saída do elétron e os valores de EDL mostraram que o tautomero O-H é melhor antioxidante pela saída de hidrogênio. A protonação é mais favorecida termodinamicamente que a desprotonação. Além disso, a energia de protonação explica, teoricamente, a baixa diferença entre a protonação do N e O. O efeito do solvente diminuiu as barreiras de energias para a isomerização nos tautomeros O-H ou N-H. Adicionalmente, foram avaliados três derivados de pirazolonas com suas capacidades antioxidantes comparadas com a edaravona, em um esforço para identificar o farmacóforo antioxidante. A capacidade antioxidante da antipirina, dipirona, fenilbutazona e edaravona foram determinadas pela inibição de dois radicais estáveis DPPH e ABTS. A edaravona e fenilbutazona foram as mais potente para a inibição de radical DPPH e ABTS que a dipirona, enquanto que a antipirina não mostrou atividade em todas as concentrações analisadas. Simultaneamente, o método TFD previu o valor do potencial antioxidante in silico para explicar a relação de estrutura-atividade (REA). Além disso, foram calculados seus valores de HOMO, EDL X-H, e energia de estabilização (DEiso). Todos os cálculos foram executados usando o programa Gaussian 03, Hyperchem 7.5, e ChemOffice 2005. Os resultados mostraram que o derivado com C-H na posição C-4 aumentou a abstração do elétron ou de hidrogênio. Finalmente, a estratégia geral empregada para planejar os novos derivados se baseou nos estudos de dezoito derivados da edaravona descritos na literatura. Os estudos de REA classificaram os compostos em três grupos, como mais ativo, ativo e menos ativo. Nove derivados foram planejados a partir do composto mais ativo selecionado pelo estudo teórico.

Estudo químico de Pterogyne nitens (Caesalpinioideae), síntese e potencial farmacológico de alcalóides guanidínicos e análogos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Nubbe natural products, source of molecular diversity for the design of new anticancer agents

Pós-graduação em Química - IQ

Mechanical and Thermal Properties of Thermoplastic Random Copolyesters Made from Lipid- Derived Medium and Long Chain Poly (x-hydroxyfatty acid) s

The physical properties of novel thermoplastic random copolyesters [-(CH2)(n)-COO-/-(CH2)(n)-COO-](x) made of long (n=12) and medium (n=8) chain length -hydroxyfatty esters [HO-(CH2)(n)-COOCH3] derived from bio-based vegetable oil feedstock are described. Poly(-hydroxy tridecanoate/-hydroxy nonanoate) P(-Me13-/-Me9-) random copolyesters (M-n=11,000-18,500 g/mol) with varying molar ratios were examined by TGA, DSC, DMA and tensile analysis, and WAXD. For the whole range of P(-Me13-/-Me9-) compositions, the WAXD data indicated an orthorhombic polyethylene-like crystal packing. Their melting characteristics, determined by DSC, varied with composition suggesting an isomorphic cocrystallization behavior. TGA of the P(-Me13-/-Me9-)s indicated improved thermal stability determined by their molar compositions. The glass transition temperature, investigated by DMA, was also found to vary with composition. The crystallinities of P(-Me13-/-Me9-)s however, were unaffected by the composition. The stiffness (Young's modulus) of these materials was found to be related to their degrees of crystallinity. (c) 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40492.

Alkylation of Histidine Residues of Bothrops jararacussu Venom Proteins and Isolated Phospholipases A(2): A Biotechnological Tool to Improve the Production of Antibodies

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Glycosomal Targets for Anti-Trypanosomatid Drug Discovery

Glycosomes are peroxisome-related organelles found in all kinetoplastid protists, including the human pathogenic species of the family Trypanosomatidae: Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Glycosomes are unique in containing the majority of the glycolytic/gluconeogenic enzymes, but they also possess enzymes of several other important catabolic and anabolic pathways. The different metabolic processes are connected by shared co-factors and some metabolic intermediates, and their relative importance differs between the parasites or their distinct life-cycle stages, dependent on the environmental conditions encountered. By genetic or chemical means, a variety of glycosomal enzymes participating in different processes have been validated as drug targets. For several of these enzymes, as well as others that are likely crucial for proliferation, viability or virulence of the parasites, inhibitors have been obtained by different approaches such as compound libraries screening or design and synthesis. The efficacy and selectivity of some initially obtained inhibitors of parasite enzymes were further optimized by structure-activity relationship analysis, using available protein crystal structures. Several of the inhibitors cause growth inhibition of the clinically relevant stages of one or more parasitic trypanosomatid species and in some cases exert therapeutic effects in infected animals. The integrity of glycosomes and proper compartmentalization of at least several matrix enzymes is also crucial for the viability of the parasites. Therefore, proteins involved in the assembly of the organelles and transmembrane passage of substrates and products of glycosomal metabolism offer also promise as drug targets. Natural products with trypanocidal activity by affecting glycosomal integrity have been reported.

Análise de pedigree e estimativas de parâmetros genéticos para características de importância econômica em bovinos Tabapuã

Pós-graduação em Genética e Melhoramento Animal - FCAV

Estudos estruturais por difração de raios X de fosfolipases A2 em presença de íons com importância funcional

Snakes from Bothrops genus are responsible for more than 90% of the ophidian accidents in Brazil. One of the main complications from this kind of accident is muscular necrosis, which is related to the action of phospholipases A2 and metalloproteases, two groups of enzymes found in the venom of these animals. Although this complication cannot be solved by serum therapy administration, a great number of studies have been performed with the attempt to know the pharmacological sites of these toxins aiming, in the future, the development of complementary treatments to serum therapy. This work proposes structural studies of bothropic phospholipases A2 (PLA2s) in the presence of ions relevant to their activity, using the X-ray crystallography technique. Recently, it was demonstrated ions, as manganese, calcium and others, interfere in the biological activity of the PLA2s. Particularly, Lys49-PLA2s in the presence of manganese ions have miotoxicity reduced. Asp49-PLA2s show catalytic activity dependent of calcium, although structural studies with a miotoxic Asp49-PLA2, BthTX-II, suggest a possible catalytic mechanism independent of calcium. Therefore, co-crystallization of BthTX-II in the presence of calcium ions and of PrTX-I in the presence of manganese ions were performed. Comparative structural studies among obtained results and others already published in the literature were performed aiming a better understanding of the structure-function relationship of these toxins. The BthTX-II with the presence of calcium do not show this ion in the loop of coordination of calcium, presence necessary to develop the catalyses. After comparison of this model with the native one, only one distortion was found, but no apparent relationship with the residues responsible for its activity. In the PrTX-I structure, regions candidates of manganese ions were also found... (Complete abstract click electronic access below)

Identificando tipos de personalidade na dança de salão

Many studies have shown a variety of benefits that the practice of Ballroom Dancing can bring, such as leisure and entertainment, the release of tension from a stressful routine, improving relationships, expanding social contacts. The rationale of this study is by the need to evaluate a different sphere of life of people involving the structure that is the personality. The man is humanized in contact with other men and the culture it is almost impossible to grow it in isolation, that is, are the social relationships that allow men to become human and her personality structure. The relationship brought about by the ballroom dancing can benefit the development of personality or simply put individuals in situations that provide a greater understanding of yourself, as this activity has characteristics that greatly facilitate social contact between people who practice it as the relationship between gentleman and lady for a dance, the contact with people in different classes, social events where it is practiced and even the music that is danced. This work aimed to be able to identify the type or types, the most common personalities exist in one group of participants in a course of Ballroom, based on the technique of Enneagram developed and disseminated by Gurdjieff, whose characteristic is to divide into nine different personality types. Participants were 42 students of the extent to ballroom dancing. We administered a questionnaire to identify the personality of each participant and then there was a second observation time the behavior of six participants in the class for confirmation of your psychological type to issofoi used a checklist developed by the author. Was also investigated whether there are differences of gender and psychological types who seek more such activity. The conclusions are that there are a large number of persons type 9, more than 42% and are predominantly male, since... (Complete abstract click electronic access below)