A Quantum Mechanics / Molecular Mechanics Study of the Protein-Ligand Interaction of two potent inhibitors of human O-GlcNAcase: PUGNAc and NAG-thiazoline

O-glycoprotein 2-acetamino-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase) hydrolyzes 2-acetamido-2-deoxy-β-D-glucopyranose (O-GlcNAc) residues of serine/threonine residues of modified proteins. O-GlcNAc is present in many intracellular proteins and appears to have a role in the etiology of several diseases including cancer, Alzheimer’s disease, and type II diabetes. In this work, we have carried out molecular dynamics (MD) simulations using a hybrid Quantum Mechanics / Molecular Mechanics (QM/MM) approach, to determine the binding of two potent inhibitors, PUGNAc and NAG, with a bacterial O-GlcNAcase. The results of these simulations show that Asp-401, Asp-298 and Asp-297 residues play an important role in the protein-inhibitor interactions. These results might be useful to design compounds with more interesting inhibitory activity on the basis of its three-dimensional structur

Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach

The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication since it protects the virus from host innate immune restriction. In particular, nonstructural protein 16 (nsp16) in complex with nsp10 is a Cap-0 binding enzyme. The heterodimer formed by nsp16-nsp10 methylates the 50 -end of virally encoded mRNAs to mimic cellular mRNAs and thus it is one of the enzymes that is a potential target for antiviral therapy. In this study, we have evaluated the mechanism of the 20 -O methylation of the viral mRNA cap using hybrid quantum mechanics/molecular mechanics (QM/MM) approach. It was found that the calculated free energy barriers obtained at M062X/6-31+G(d,p) is in agreement with experimental observations. Overall, we provide a detailed molecular analysis of the catalytic mechanism involving the 20 -O methylation of the viral mRNA cap and, as expected, the results demonstrate that the TS stabilization is critical for the catalysis

Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESThe absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventi903464472CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESSEM INFORMAÇÃOSEM INFORMAÇÃOSEM INFORMAÇÃOThe authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES (CAPES) for financial suppor

Análise espacial do crime ambiental em Manaus, amazonas no período de 2014-2017 / Spatial analysis of environmental crime in Manaus, amazonas in the period 2014-2017

Os crimes ambientais contrapõem as leis vigentes e geram transtornos à sociedade em geral e uma das polêmicas referentes ao uso do direito penal no cuidado ao  meio ambiente é o fato de que as autoridades públicas em geral não se posicionam de modo eficiente para garantir a proteção ambienta. Diante disso, esta pesquisa teve a finalidade de identificar os crimes ambientais a partir dos boletins de ocorrência produzidos pela Polícia Civil no Sistema Integrado de Segurança Pública do Estado do Amazonas, no período de 2014 a 2107, na cidade de Manaus. Para tanto se partiu da hipótese que existia ligação entre crime, densidade demográfica e indicadores de desenvolvimento humano. Os registros policiais obtidos continham latitude e longitude e, por conseguinte foram tratados no software Argcis que possibilitou a produção de mapas específicos; tal metodologia tornou possível quantificar os crimes ambientais, além de apontar as maiores concentrações de cada evento, a localização espacial e o perfil do agente executor dos delitos averiguados. Concluiu-se que os principais crimes contrários à natureza estão ligados à fauna e flora e que existe para determinadas tipologias descritas na lei 9.605/98 uma relação direta de proporcionalidade entre densidade demográfica e criminalidade. Nesse sentido, os órgãos ligados à prevenção do meio ambiente, no maior território da Amazônia, devem continuar a direcionar suas políticas de forma integrada e combater com a sociedade os danos voltados ao meio ambiente

The occurrence of heavy metals in a water resource in benjamin constant, Amazonas, Brazil / The occurrence of heavy metals in a water resource in benjamin constant, Amazonas, Brazil

Disordered population growth has led to a progressive reduction in environmental quality in water ecosystems. Thus, it aimed to know the occurrence of heavy metals and their influence on the levels of environmental degradation in a water ecosystem in the municipality of Benjamin Constant-AM. The samples were collected at six specific points, with the lowest and highest urban concentration, in two periods that corresponded to the lowest and highest precipitation, using chemical parameters. Signs of environmental degradation were noted, such as deforestation and water pollution by domestic waste throughout the effluent, with values higher than the current legislation.

Obtenção E Caracterização De Complexo De Inclusão De ?-Ciclodextrina E Eugenol / Preparation And Characterization Of ?-Cyclodextrin Inclusion Complex Of Eugenol

O eugenol é um fenilpropanóide presente em óleos essenciais de diversas plantas, cabendo destaque ao Cravo-da-Índia. Esta substância possui considerável importância farmacológica devido às suas atividades antioxidantes, porém, sua alta volatilização e instabilidade físico-química a fatores ambientais (luz, oxigênio e calor) têm dificultado seu uso tal qual nas formulações farmacêuticas. Neste contexto, buscou-se no presente trabalho produzir complexos de inclusão de eugenol em ?-ciclodextrina a fim de amenizar tais limitações. A complexação foi realizada por meio de coprecipitação e evaporação do solvente, em proporção molar de eugenol:?-ciclodextrina (1:1). Os complexos foram caracterizados por Difratometria de Raios-X (DRX); Espectroscopia de Infravermelho por Transformada de Fourier (FTIR). Os resultados revelaram que é possível caracterizar a interação hóspede/hospedeiro e, portanto, o êxito no processo de complexação, a partir de dados difratométricos (DRX) e espectrais (FTIR), o que torna o uso destas duas técnicas adequado para pesquisas no desenvolvimento de compostos com interesse biológico

The catalytic mechanism of glyceraldehyde 3-phosphate dehydrogenase from Trypanosoma cruzi elucidated via the QM/MM approach

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as a key enzyme involved in glycolysis processes for energy production in the Trypanosoma cruzi parasite. This enzyme catalyses the oxidative phosphorylation of glyceraldehyde 3-phosphate (G3P) in the presence of inorganic phosphate (Pi) and nicotinamide adenosine dinucleotide (NAD+). The catalytic mechanism used by GAPDH has been intensively investigated. However, the individual roles of Pi and the C3 phosphate of G3P (Ps) sites, as well as some residues such as His194 in the catalytic mechanism, remain unclear. In this study, we have employed Molecular Dynamics (MD) simulations within hybrid quantum mechanical/molecular mechanical (QM/MM) potentials to obtain the Potential of Mean Force of the catalytic oxidative phosphorylation mechanism of the G3P substrate used by GAPDH. According to our results, the first stage of the reaction (oxidoreduction) takes place in the Pi site (energetically more favourable), with the formation of oxyanion thiohemiacetal and thioacylenzyme intermediates without acidbase assistance of His194. Analysis of the interaction energy by residues shows that Arg249 has an important role in the ability of the enzyme to bind the G3P substrate, which interacts with NAD+ and other important residues, such as Cys166, Glu109, Thr167, Ser247 and Thr226, in the GAPDH active site. Finally, the inhibition mechanism of the GAPDH enzyme by the 3-(p-nitrophenoxycarboxyl)-3-ethylene propyl dihydroxyphosphonate inhibitor was investigated in order to contribute to the design of new inhibitors of GAPDH from Trypanosoma cruzi