Purine nucleoside phosphorylase from Schistosoma mansoni in complex with ribose-1-phosphate

A binary complex between a low-molecular-weight purine nucleoside phosphorylase and ribose-1-phosphate is described for the first time and comparisons with known ternary complexes are drawn

Crystal structure of Leishmania tarentolae hypoxanthine-guanine phosphoribosyltransferase

<p>Abstract</p> <p>Background</p> <p>Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (EC 2.4.2.8) is a central enzyme in the purine recycling pathway. Parasitic protozoa of the order <it>Kinetoplastida </it>cannot synthesize purines <it>de novo </it>and use the salvage pathway to synthesize purine bases, making this an attractive target for antiparasitic drug design.</p> <p>Results</p> <p>The glycosomal HGPRT from <it>Leishmania tarentolae </it>in a catalytically active form purified and co-crystallized with a guanosine monophosphate (GMP) in the active site. The dimeric structure of HGPRT has been solved by molecular replacement and refined against data extending to 2.1 Å resolution. The structure reveals the contacts of the active site residues with GMP.</p> <p>Conclusion</p> <p>Comparative analysis of the active sites of <it>Leishmania </it>and human HGPRT revealed subtle differences in the position of the ligand and its interaction with the active site residues, which could be responsible for the different reactivities of the enzymes to allopurinol reported in the literature. The solution and analysis of the structure of <it>Leishmania </it>HGPRT may contribute to further investigations leading to a full understanding of this important enzyme family in protozoan parasites.</p

Ciência e inovação

Necessity exerted a selection pressure on the human species, who learned to research, to accumulate knowledge and to innovate. Such strategy was key to human evolution; and science and innovation are the two complemetary sidesof the same coin. In Brazil, after the predatory phase of the colonial rule had ended, such strategy of accumulating knowledge as a premise of innovation can be noticed in the post-Second World War period, when investments were made in science and technology to ensure sovereignty as well as social and economic development. The model adopted then was that of creating a solid training program both in the country and abroad, along with a support program for scientific research. Thus, at their early phase those programs sought to promote the generation of knowledge, which eventually would lead to itsuse in innovation. Despite the lack of consensus in relation to the indicators used to measure and compare our level of scientific and technological development, the results indicate that we have achieved a respectable stature – both qualitative and quantitative-wise – of generating knowledge needed for us to take a leap forward in terms of innovation, in a context of a modern society seeking social and economic devopment on sustainable bases.Sob a pressão seletiva das necessidades, a espécie humana aprendeu a pesquisar, acumular conhecimento e inovar. Essa foi a estratégia central na evolução humana, que tem a ciência e a inovação como faces complementares da mesma moeda. No Brasil, superada a fase predatória colonial, essa estratégia de acumulação de conhecimento como premissa da inovaçãose faz sentir após a Segunda Guerra Mundial, com os investimentos em ciência e tecnologia para garantir a soberania e o desenvolvimento econômico e social. O modelo adotado foi o de se criar um forte programa de capacitação no país e no exterior juntamente com um programa de apoioà pesquisa científica, promovendo-se numa primeira etapa a geração de conhecimento que, fatalmente, levaria à sua utilização na inovação. Apesar da falta de consenso em relação aos indicadores utilizados para medir e comparar nosso grau de desenvolvimento científico e tecnológico, os resultados sugerem que já alcançamos um estágio respeitável, tanto doponto de vista qualitativo quanto quantitativo, na geração do conhecimento necessário para darmos um salto em relação à inovação no contexto de uma sociedade moderna que busca o desenvolvimento econômico e social em bases sustentáveis

Structure-based drug discovery for tropical diseases

Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.FAPESPCNP

The allosteric transition of glucosamine-6-phosphate deaminase: the structure of the T state at 2.3 Å resolution

AbstractBackground: The allosteric hexameric enzyme glucosamine-6-phosphate deaminase from Escherichia coli catalyses the regulatory step of N-acetylglucosamine catabolism, which consists of the isomerisation and deamination of glucosamine 6-phosphate (GlcN6P) to form fructose 6-phosphate (Fru6P) and ammonia. The reversibility of the catalysis and its rapid-equilibrium random kinetic mechanism, among other properties, make this enzyme a good model for studying allosteric processes.Results: Here we present the structure of P6322 crystals, obtained in sodium acetate, of GlcN6P deaminase in its ligand-free T state. These crystals are very sensitive to X-ray radiation and have a high (78%) solvent content. The active-site lid (residues 162–185) is highly disordered in the T conformer; this may contribute significantly to the free-energy change of the whole allosteric transition. Comparison of the structure with the crystallographic coordinates of the R conformer (Brookhaven Protein Data Bank entry 1dea) allows us to describe the geometrical changes associated with the allosteric transition as the movement of two rigid entities within each monomer. The active site, located in a deep cleft between these two rigid entities, presents a more open geometry in the T conformer than in the R conformer.Conclusions: The differences in active-site geometry are related to alterations in the substrate-binding properties associated with the allosteric transition. The rigid nature of the two mobile structural units of each monomer seems to be essential in order to explain the observed kinetics of the deaminase hexamer. The triggers for both the homotropic and heterotropic allosteric transitions are discussed and particular residues are assigned to these functions. A structural basis for an entropic term in the allosteric transition is an interesting new feature that emerges from this study

Integrating virtual and high-throughput screening: opportunities and challenges in drug research and development

High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.FAPESPCNP

Modern drug discovery technologies: opportunities and challenges in lead discovery

The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery projects. The definition and assessment of both chemical and biological space have revitalized the screening process model and emphasized the importance of exploring the intrinsic complementary nature of classical and\ud modern methods in drug research. In this context, the widespread use of combinatorial chemistry and sophisticated screening methods for the discovery of lead compounds has created a large demand for small organic molecules that act on specific drug targets.\ud Modern drug discovery involves the employment of a wide variety of technologies and expertise in multidisciplinary research teams. The synergistic effects between experimental and computational approaches on the selection and optimization of bioactive compounds emphasize the importance of the integration of advanced technologies in drug discovery programs. These technologies (VS, HTS, SBDD, LBDD, QSAR, and so on) are complementary in the sense that they have mutual goals, thereby the combination of both empirical and in silico efforts is feasible at many different levels of lead optimization and new chemical entity (NCE) discovery. This paper provides a brief perspective on the evolution and use of key drug design technologies, highlighting opportunities and challenges

Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.State of Sao Paulo Research Foundation (FAPESP)State of Sao Paulo Research Foundation (FAPESP)National Council for Scientific and Technological Development (CNPq), BrazilNational Council for Scientific and Technological Development (CNPq), Brazi

Virtual screening and its integration with modern drug design technologies

Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics- and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.FAPESPCNP

Prêmio Nobel de Química de 2012: a transdução celular de sinais por estímulos externos

O Prêmio Nobel de Química foi concedido para 162 cientistas entre 1901 e 2012. Jacobus Henricus van't Hoff foi o primeiro laureado, em 1901, e Frederick Sanger o único premiado duas vezes, em 1958 e 1980. O de 2012 foi atribuído aos pesquisadores americanos Robert J. Lefkowitz e Brian K. Kobilka por seus estudos sobre os receptores acoplados à proteína G (GPCRs, sigla em inglês para G-protein-coupled receptors). Estas fazem parte de uma superfamília de proteínas que estão acopladas a receptores celulares e, quando ativadas, interferem na transdução de sinais, resultando em processos de ativação de importantes eventos intracelulares por estímulos externos. Este artigo explica o que são os GPCRs, como eles atuam nas células e também a contribuição dos dois laureados para o avanço do conhecimento sobre esses receptores