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A computer-driven approach to discover natural product leads for methicillin-resistant staphylococcus aureus infection therapy †
Publication . Dias, Tiago; Gaudêncio, Susana P.; Pereira, Florbela; UCIBIO - Applied Molecular Biosciences Unit; LAQV@REQUIMTE; DQ - Departamento de Química; MDPI - Multidisciplinary Digital Publishing Institute
The risk of methicillin-resistant Staphylococcus aureus (MRSA) infection is increasing in both the developed and developing countries. New approaches to overcome this problem are in need. A ligand-based strategy to discover new inhibiting agents against MRSA infection was built through exploration of machine learning techniques. This strategy is based in two quantitative structure–activity relationship (QSAR) studies, one using molecular descriptors (approach A) and the other using descriptors (approach B). In the approach A, regression models were developed using a total of 6645 molecules that were extracted from the ChEMBL, PubChem and ZINC databases, and recent literature. The performance of the regression models was successfully evaluated by internal and external validation, the best model achieved R 2 of 0.68 and RMSE of 0.59 for the test set. In general natural product (NP) drug discovery is a time-consuming process and several strategies for dereplication have been developed to overcome this inherent limitation. In the approach B, we developed a new NP drug discovery methodology that consists in frontloading samples with 1D NMR descriptors to predict compounds with antibacterial activity prior to bioactivity screening for NPs discovery. The NMR QSAR classification models were built using 1D NMR data ( 1 H and 13 C) as descriptors, from crude extracts, fractions and pure compounds obtained from actinobacteria isolated from marine sediments collected off the Madeira Archipelago. The overall predictability accuracies of the best model exceeded 77% for both training and test sets.
Risk assessment of pesticides in estuaries: a review addressing the persistence of an old problem in complex environments
Publication . Cuevas, Nagore; Martins, Marta; Costa, Pedro M.; DCV - Departamento de Ciências da Vida; UCIBIO - Applied Molecular Biosciences Unit; DCEA - Departamento de Ciências e Engenharia do Ambiente; MARE - Centro de Ciências do Mar e do Ambiente; DQ - Departamento de Química; Springer
Estuaries, coastal lagoons and other transition ecosystems tend to become the ultimate reservoirs of pollutants transported by continental runoff, among which pesticides constitute the class of most concern. High amounts of dissolved and particulated organic matter greatly contribute to the accumulation of pesticides that eventually become trapped in sediments or find their way along food chains. Perhaps not so surprisingly, it is common to find elevated levels of pesticides in estuarine sediments decades after their embargo. Still, it remains challenging to address ecotoxicity in circumstances that invariably imply mixtures of contaminants and multiple factors affecting bioavailability. Despite advances in methods for detecting pesticides in waters, sediments and organisms, chemical data alone are insufficient to predict risk. Many researchers have been opting for ex situ bioassays that mimic the concentrations of pesticides in estuarine waters and sediments using a range of ecologically relevant model organisms, with emphasis on fish, molluscs and crustaceans. These experimental procedures unravelled novel risk factors and important insights on toxicological mechanisms, albeit with some prejudice of ecological relevance. On the other hand, in situ bioassays, translocation experiments and passive biomonitoring strive to spot causality through an intricate mesh of confounding factors and cocktails of pollutants. Seemingly, the most informative works are integrative approaches that combine different assessment strategies, multiple endpoints and advanced computational and geographical models to determine risk. State-of-art System Biology approaches combining high-content screening approaches involving “omics” and bioinformatics, can assist discovering and predicting novel Adverse Outcome Pathways that better reflect the cumulative risk of persisting and emerging pesticides among the wide range of stressors that affect estuaries.
Multifunctional microfluidic chip for optical nanoprobe based RNA detection - Application to Chronic Myeloid Leukemia
Publication . Alves, Pedro Urbano; Vinhas, Raquel; Fernandes, Alexandra R.; Birol, Semra Zuhal; Trabzon, Levent; Bernacka-Wojcik, Iwona; Igreja, Rui; Lopes, Paulo; Baptista, Pedro Viana; Águas, Hugo; Fortunato, Elvira; Martins, Rodrigo; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; CENIMAT-i3N - Centro de Investigação de Materiais (Lab. Associado I3N); DCM - Departamento de Ciência dos Materiais; Nature Publishing Group
Many diseases have their treatment options narrowed and end up being fatal if detected during later stages. As a consequence, point-of-care devices have an increasing importance for routine screening applications in the health sector due to their portability, fast analyses and decreased cost. For that purpose, a multifunctional chip was developed and tested using gold nanoprobes to perform RNA optical detection inside a microfluidic chip without the need of molecular amplification steps. As a proof-of-concept, this device was used for the rapid detection of chronic myeloid leukemia, a hemato-oncological disease that would benefit from early stage diagnostics and screening tests. The chip passively mixed target RNA from samples, gold nanoprobes and saline solution to infer a result from their final colorimetric properties. An optical fiber network was used to evaluate its transmitted spectra inside the chip. Trials provided accurate output results within 3 min, yielding signal-to-noise ratios up to 9 dB. When compared to actual state-of-art screening techniques of chronic myeloid leukemia, these results were, at microscale, at least 10 times faster than the reported detection methods for chronic myeloid leukemia. Concerning point-of-care applications, this work paves the way for other new and more complex versions of optical based genosensors.
Thermodynamic and functional characterization of the periplasmic triheme cytochrome PpcA from Geobacter metallireducens
Publication . Fernandes, Tomás M.; Morgado, Leonor; Salgueiro, Carlos A.; UCIBIO - Applied Molecular Biosciences Unit; DQ - Departamento de Química; Biochemical Society | Portland Press
The Geobacter metallireducens bacterium can couple the oxidation of a wide range of compounds to the reduction of several extracellular electron acceptors, including pollutants or electrode surfaces for current production in microbial fuel cells. For these reasons, G. metallireducens are of interest for practical biotechnological applications. The use of such electron acceptors relies on a mechanism that permits electrons to be transferred to the cell exterior. The cytochrome PpcA from G. metallireducens is a member of a family composed of five periplasmic triheme cytochromes, which are important to bridge the electron transfer from the cytoplasmic donors to the extracellular acceptors. Using NMR and visible spectroscopic techniques, a detailed thermodynamic characterization of PpcA was obtained, including the determination of the heme reduction potentials and their redox and redox-Bohr interactions. These parameters revealed unique features for PpcA from G. metallireducens compared with other triheme cytochromes from different microorganisms, namely the less negative heme reduction potentials and concomitant functional working potential ranges. It was also shown that the order of oxidation of the hemes is pH-independent, but the protein is designed to couple e − /H + transfer exclusively at physiological pH.
Electron Ionization of Imidazole and Its Derivative 2-Nitroimidazole
Publication . Meißner, Rebecca; Feketeová, Linda; Ribar, Anita; Fink, Katharina; Limão-Vieira, Paulo; Denifl, Stephan; DF – Departamento de Física; CeFITec – Centro de Física e Investigação Tecnológica; Elsevier Science B.V., Amsterdam.
Imidazole (IMI) is a basic building block of many biologically important compounds. Thus, its electron ionization properties are of major interest and essential for the comparison with other molecular targets containing its elemental structure. 2-Nitroimidazole (2NI) contains the imidazole ring together with nitrogen dioxide bound to the C2 position, making it a radiosensitizing compound in hypoxic tumors. In the present study, we investigated electron ionization of IMI and 2NI and determined the mass spectra, the ionization energies, and appearance energies of the most abundant fragment cations. The experiments were complemented by quantum chemical calculations on the thermodynamic thresholds and potential energy surfaces, with particular attention to the calculated transition states for the most important dissociation reactions. In the case of IMI, substantially lower threshold values (up to ~ 1.5 eV) were obtained in the present work compared to the only available previous electron ionization study. Closer agreement was found with recent photon ionization values, albeit the general trend of slightly higher values for the case of electron ionization. The only exception for imidazole was found in the molecular cation at m/z 40 which is tentatively assigned to the quasi-linear HCCNH+/ HCNCH+. Electron ionization of 2NI leads to analogous fragment cations as in imidazole, yet different dissociation pathways must be operative due to the presence of the NO2 group. Regarding the potential radiosensitization properties of 2NI, electron ionization is characterized by dominant parent cation formation and release of the neutral NO radical. [Figure not available: see fulltext.].
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Fundação para a Ciência e a Tecnologia
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5876
Número da atribuição
147258