BACKGROUND Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host’s defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite. OBJECTIVES This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features. METHODS Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations. FINDINGS We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates. MAIN CONCLUSION Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites.

Resumo Objetivo Descrever o estágio do envelhecimento populacional no município do Rio de Janeiro. Métodos Estudo ecológico tendo como unidades de observação os 160 bairros que compõem o município, utilizando indicadores sociais e demográficos construídos a partir de informações do Censo 2010. Realizou-se análise exploratória por meio de mapas temáticos e determinou-se a dependência espacial pelo Índice de Moran Global. Para agrupar bairros em estágios semelhantes do envelhecimento foi realizada uma análise de agrupamento a partir do método K-means. Resultados Encontraram-se três grupos de bairros em estágios diferentes de envelhecimento populacional, identificando-se uma tendência espacial no sentido oeste-leste com os bairros da “Zona Sul” se encontrando no estágio mais avançado de envelhecimento. Conclusão O estudo identificou as diferenças no processo de envelhecimento populacional e na composição etária dos bairros, apontando para a necessidade de políticas de saúde pública específicas que contemplem as particularidades desse processo em cada localidade, visando garantir um envelhecimento sustentável.

Abstract Objective Describe the stage of population aging in the city of Rio de Janeiro. Methods Ecological study with the 160 city neighborhoods as observational units, using social and demographic indicators built with information from the 2010 census. The exploratory analysis was undertaken with thematic maps, and the spatial dependence was measured with the Global Moran’s Index. K-means clustering was used for grouping neighborhoods with similar aging stages. Results Three neighborhood clusters in different stages of population aging were found and a spatial trend in the west-east direction was identified, with neighborhoods in the ‘South Zone’ in a more advanced stage of population aging. Conclusion The study identified differences in the population aging process and in the age composition of neighborhoods, indicating the need for specific public health policies that allow for the particularities of this process in each location, aiming a sustainable population aging.

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.

Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.

A integrina VLA-4 (integrina α4β1) participa da fisiopatologia de uma grande variedade de doenças, incluindo asma, esclerose múltipla, artrite reumatóide e diabetes. A seletividade de ligantes por essa integrina permanece ainda um problema sem resposta, principalmente devido ao fato das estruturas 3D da maioria delas serem ainda desconhecida. Inicialmente, construímos um modelo computacional tridimensional do sítio ativo da integrina α4β1, utilizando a estrutura cristalográfica da integrina αVβ3 como molde. Após, realizamos um estudo por docking molecular usando um conjunto de sete antagonistas de α4β1 derivados de 4-[N'-(2-metilfenil)ureido]fenilacetil, avaliando os seus modos de ligação. A técnica de dinâmica molecular foi utilizada de modo a aumentar a eficiência da exploração do perfil energético obtido pelo algoritmo de docking. Segundo a nossa análise, os compostos foram sistematicamente agrupados em dois modos de ligação principais, sendo a conformação estendida o modo prevalente de ligação dos antagonistas no sítio. Cálculos de energia livre também confirmaram essa constatação. Esse estudo aumenta a compreensão dos mecanismos de ligação dessa família de antagonistas e pode fornecer informações úteis ao desenho racional de fármacos específicos para o VLA-4.

The VLA-4 antigen (α4β1 integrin) is involved in the pathophysiology of a variety of diseases including asthma, multiple sclerosis, rheumatoid arthritis and diabetes. The ligand selectivity toward this integrin remains a difficult problem, mainly due to the fact that 3D structures of most integrins are still unknown. We initially built a 3D computational model of the α4β1 ligand binding site, taking the crystal structure of the integrin αVβ3 as template. Then, we performed a computational study on a set of seven α4β1 antagonists, evaluating the binding modes of 4-[N'-(2-methylphenyl)ureido]phenylacetyl and derivatives by molecular docking. Molecular dynamics simulations were used to improve the receptor-ligand energy landscape exploration by the docking algorithm. The compounds were systematically arranged in two main binding modes, and in all cases, pointed out that these antagonists preferably bind to the α4β1 integrin active site in an extended conformation that resembles the one in solution. LIE (linear interaction energy) calculations also confirmed this statement given that the most prevailing binding mode is also the energetically most favored one. This study benefits the comprehension of the mechanism of this family of antagonists and may provide useful information for rational drug design.