Structure-based drug design studies of the interactions ofent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparumsarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosawere tested in silico against the Plasmodium falciparumCa2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

A programme for computer aided identification of Phlebotomine sandflies of the Americas (CIPA): presentation and check-list of American species

The CIPA programme is a collaborative project including two entomologists from France and seven South and Central America countries. Its objective is the development of an expert system for computer aided identification of phlebotomine sandflies from the Americas. It also includes the formation of data bases for bibliographic, taxonomic and biogeographic data. Participant consensus on taxonomic prerequisites, standardization in bibliographic data collections and selection of descriptive variables for the final programme has been established through continous communication among participants and annual meetings. The adopted check-list of American sandflies presented here includes 386 specific taxa, ordered into genera and 28 sub-genera or species groups.

Accuracy of computer-aided ultrasound as compared with magnetic resonance imaging in the evaluation of nonalcoholic fatty liver disease in obese and eutrophic adolescents

AbstractObjective:To compare the accuracy of computer-aided ultrasound (US) and magnetic resonance imaging (MRI) by means of hepatorenal gradient analysis in the evaluation of nonalcoholic fatty liver disease (NAFLD) in adolescents.Materials and Methods:This prospective, cross-sectional study evaluated 50 adolescents (aged 11–17 years), including 24 obese and 26 eutrophic individuals. All adolescents underwent computer-aided US, MRI, laboratory tests, and anthropometric evaluation. Sensitivity, specificity, positive and negative predictive values and accuracy were evaluated for both imaging methods, with subsequent generation of the receiver operating characteristic (ROC) curve and calculation of the area under the ROC curve to determine the most appropriate cutoff point for the hepatorenal gradient in order to predict the degree of steatosis, utilizing MRI results as the gold-standard.Results:The obese group included 29.2% girls and 70.8% boys, and the eutrophic group, 69.2% girls and 30.8% boys. The prevalence of NAFLD corresponded to 19.2% for the eutrophic group and 83% for the obese group. The ROC curve generated for the hepatorenal gradient with a cutoff point of 13 presented 100% sensitivity and 100% specificity. As the same cutoff point was considered for the eutrophic group, false-positive results were observed in 9.5% of cases (90.5% specificity) and false-negative results in 0% (100% sensitivity).Conclusion:Computer-aided US with hepatorenal gradient calculation is a simple and noninvasive technique for semiquantitative evaluation of hepatic echogenicity and could be useful in the follow-up of adolescents with NAFLD, population screening for this disease as well as for clinical studies.

Modelagem Molecular: Uma Ferramenta para o Planejamento Racional de Fármacos em Química Medicinal

The molecular basis of modern therapeutics consist in the modulation of cell function by the interaction of microbioactive molecules as drug cells macromolecules structures. Molecular modeling is a computational technique developed to access the chemical structure. This methodology, by means of the molecular similarity and complementary paradigm, is the basis for the computer-assisted drug design universally employed in pharmaceutical research laboratories to obtain more efficient, more selective, and safer drugs. In this work, we discuss some methods for molecular modeling and some approaches to evaluate new bioactive structures in development by our research group.

A química medicinal na próxima década

Medicinal chemistry is multi, trans and inter disciplinary on its essence. It has a great deal of challenging Brazilian chemists in the next decade. The pharmacy school is essentially attached and has an important role in the development on the field that is still in domain of big pharmaceutical industries. This work shows the challenges to face and directions to jointly follow for a myriad of researchers throughout the country. The unnamed science has to work out through specific objectives in order to diminish the problems associated with human being health. A brief history is presented where the main goal is to devise chemistry, as a natural science, and many other interfaced disciplines.

A feature-based object-oriented expert system to model and support product design

In this paper a computer program to model and support product design is presented. The product is represented through a hierarchical structure that allows the user to navigate across the product’s components, and it aims at facilitating each step of the detail design process. A graphical interface was also developed, which shows visually to the user the contents of the product structure. Features are used as building blocks for the parts that compose the product, and object-oriented methodology was used as a means to implement the product structure. Finally, an expert system was also implemented, whose knowledge base rules help the user design a product that meets design and manufacturing requirements.

Antitumor activity of chemical modified natural compounds

Search of new activity substances starting from chemotherapeutic agents, continously appears in international literature. Perhaps this search has been done more frequently in the field of anti-tumor chemotherapy on account of the unsuccess in saving advanced stage patients. The new point in this matter during the last decade was computer aid in planning more rational drugs. In near future "the accessibility of supercomputers and emergence of computer net systems, willopen new avenues to rational drug design" (Portoghese, P. S. J. Med. Chem. 1989, 32, 1). Unknown pharmacological active compounds synthetized by plants can be found even without this eletronic devices, as tradicional medicine has pointed out in many contries, and give rise to a new drug. These compounds used as found in nature or after chemical modifications have produced successful experimental medicaments as FAA, "flavone acetic acid" with good results as inibitors of slow growing animal tumors currently in preclinical evaluation for human treatment. In this lecture some international contributions in the field of chemical modified compounds as antineoplasic drugs will be examined, particularly those done by Brazilian researches.

Introdução a modelagem molecular de fármacos no curso experimental de química farmacêutica

Molecular Modeling is an important tool in drug design and it is very useful to predict biological activity from a library of compounds. A wide variety of computer programs and methods have been developed to visualize the tridimensional geometry and calculate physical properties of drugs. In this work, we describe a practical approach of molecular modeling as a powerful tool to study structure-activity relationships of drugs, including some antibacterials, hormones, cholinergic and adrenergic agents. At first, the students learn how to draw 3D structures and use them to perform conformational and molecular analysis. Thus, they compare drugs with similar pharmacological activity by superimposing one structure on the top of another and evaluate the geometry and physical properties.

Protein folding: a perspective for biology, medicine and biotechnology

At the present time, protein folding is an extremely active field of research including aspects of biology, chemistry, biochemistry, computer science and physics. The fundamental principles have practical applications in the exploitation of the advances in genome research, in the understanding of different pathologies and in the design of novel proteins with special functions. Although the detailed mechanisms of folding are not completely known, significant advances have been made in the understanding of this complex process through both experimental and theoretical approaches. In this review, the evolution of concepts from Anfinsen's postulate to the "new view" emphasizing the concept of the energy landscape of folding is presented. The main rules of protein folding have been established from in vitro experiments. It has been long accepted that the in vitro refolding process is a good model for understanding the mechanisms by which a nascent polypeptide chain reaches its native conformation in the cellular environment. Indeed, many denatured proteins, even those whose disulfide bridges have been disrupted, are able to refold spontaneously. Although this assumption was challenged by the discovery of molecular chaperones, from the amount of both structural and functional information now available, it has been clearly established that the main rules of protein folding deduced from in vitro experiments are also valid in the cellular environment. This modern view of protein folding permits a better understanding of the aggregation processes that play a role in several pathologies, including those induced by prions and Alzheimer's disease. Drug design and de novo protein design with the aim of creating proteins with novel functions by application of protein folding rules are making significant progress and offer perspectives for practical applications in the development of pharmaceuticals and medical diagnostics.

Pharmacological Approaches to Antitrypanosomal Chemotherapy

There is an urgent need for new drugs for the chemotherapy of human African trypanosomiasis, Chagas disease and leishmaniasis. Progress has been made in the identification and characterization of novel drug targets for rational chemotherapy and inhibitors of trypanosomatid glycosomal enzymes, trypanothione reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, cysteine proteases and of the purine and sterol biosynthetic pathways. However, less attention has been paid to the pharmacological aspects of drug design or to the use of drug delivery systems in the chemotherapy of African trypanosomiasis and Chagas disease. A review of research on pharmacology and drug delivery systems shows that there are new opportunities for improving the chemotherapy of these diseases.

Effects of Trypanosoma brucei tryptophanyl-tRNA synthetases silencing by RNA interference

The kinetoplast genetic code deviates from the universal code in that 90% of mitochondrial tryptophans are specified by UGA instead of UGG codons. A single nucleus-encoded tRNA Trp(CCA) is used by both nuclear and mitochondria genes, since all kinetoplast tRNAs are imported into the mitochondria from the cytoplasm. To allow decoding of the mitochondrial UGA codons as tryptophan, the tRNA Trp(CCA) anticodon is changed to UCA by an editing event. Two tryptophanyl tRNA synthetases (TrpRSs) have been identified in Trypanosoma brucei: TbTrpRS1 and TbTrpRS2 which localize to the cytoplasm and mitochondria respectively. We used inducible RNA interference (RNAi) to assess the role of TbTrpRSs. Our data validates previous observations of TrpRS as potential drug design targets and investigates the RNAi effect on the mitochondria of the parasite.

Avaliação do volume da placenta no primeiro trimestre de gestação por meio da ultrassonografia tridimensional utilizando o método XI VOCAL

OBJETIVO: Determinar valores de referência para o volume da placenta entre 7 e 10 semanas e 6 dias de gestação por meio da ultrassonografia tridimensional utilizando o método XI VOCAL (eXtended Imaging Virtual Organ Computer-aided Analysis). MATERIAIS E MÉTODOS: Realizou-se estudo de corte transversal com 70 gestantes normais entre 7 e 10 semanas e 6 dias. Para o cálculo de volume, utilizou-se o método XI VOCAL com delimitação de dez planos adjacentes. Foram determinadas médias, medianas, desvios-padrão, valores máximo e mínimo para o volume da placenta. Para avaliar a correlação do volume da placenta com a idade gestacional, foi criado gráfico de dispersão, sendo o ajuste realizado pelo coeficiente de determinação (R²). RESULTADOS: A média do volume da placenta variou de 4,6 cm³ (2,6-8,6 cm³) a 28,9 cm³ (11,4-66,9 cm³). O volume da placenta (VP) se mostrou altamente correlacionado com a idade gestacional (IG), sendo o melhor ajuste com a regressão exponencial [VP = exp(0,582 × IG + 0,063); R² = 0,82]. CONCLUSÃO: Valores de referência para o volume da placenta no primeiro trimestre de gestação utilizando o método XI VOCAL foram determinados.

Reprodutibilidade interobservador dos índices vasculares do Doppler de amplitude tridimensional do embrião entre 7 e 10 semanas e 6 dias de gestação

OBJETIVO: Avaliar a reprodutibilidade interobservador dos índices de vascularização do Doppler de amplitude tridimensional (Doppler de amplitude 3D) no primeiro trimestre de gestação. MATERIAIS E MÉTODOS: Realizou-se estudo de reprodutibilidade com 32 gestantes normais entre 7 e 10 semanas e 6 dias. Para o cálculo do volume tridimensional dos embriões utilizou-se o método VOCAL (Virtual Organ Computer-aided AnaLysis) com ângulo de rotação de 12°. Em seguida obtiveram-se, automaticamente, os três índices vasculares do Doppler de amplitude 3D: índice de vascularização (VI), índice de fluxo (FI) e índice de vascularização e fluxo (VFI). Para o cálculo da variabilidade interobservador, um examinador realizou uma segunda medida dos 32 embriões e um segundo examinador realizou uma terceira medida dos mesmos volumes, ambos desconhecendo os resultados do outro. Utilizaram-se, para análise estatística, o coeficiente de correlação intraclasse (CCI) e gráficos de Bland-Altman. RESULTADOS: Observou-se boa reprodutibilidade interobservador dos três índices vasculares. O VI apresentou CCI = 0,9 e média da diferença = -1,1; o FI apresentou CCI = 0,9 e média da diferença = -0,5; e o VFI apresentou CCI = 0,9 e média da diferença = -1,1. CONCLUSÃO: Os índices vasculares do Doppler de amplitude 3D do embrião no primeiro trimestre de gestação foram altamente reprodutíveis, em especial o FI.