1,721,045 research outputs found
Anti-trypanosomatidal drug discovery: a challenge for structural biology
Get PDFDrug discovery and development is a lifelong challenge; the modern approach in the drug discovery process relies on the identification, validation and targeting of specific, unique and druggable molecular targets. So far, huge efforts have been made in order to maximize the number of active compounds identified in the lowest time possible, as in the case of large scale high-throughput screenings (HTS) or fragment-based screenings (FBS); at the same time computational tools together with biophysical methods, as X-ray crystallography, evolved so fast to make structure-based drug design (SBDD) a primary approach for drug development. These colossal knowledge and technology are now fundamental for the advancement in medicinal chemistry.
The line of research on which this work is focused regards some of the most life-threatening and neglected diseases, globally named Neglected tropical diseases, namely Leishmaniasis, Human Africa trypanosomiasis (HAT) and American trypanosomiasis. The causative agents are all belonging to the parasitic family of Trypanosomatids and even if phenotypical characteristics are different from species to species, they all share unique and specific molecular features which can be targeted for the identification and development of new broad-spectrum drugs, in order to supersede current therapies, endowed with high toxicity and inefficacy profiles.
With this aim, the trypanothione reductase (TR), a NADPH-dependent flavoenzyme, has been targeted as it fulfills all the requirements to be considered a good drug target: it is unique, as is present only in trypanosomatidal species and absent in the host, essential, playing a central role in the redox equilibrium of parasites and it is druggable, as can be efficiently addressed, and thus inhibited, by specific compounds.
Employing different approaches, new active hit compounds against TR have been identified; a spiro-containing derivative, Compound 1, has been identified via HTS and fully characterized (Turcano et al., 2020). Its competitive mechanism of inhibition has been assessed and confirmed by SPR and X-ray crystallography respectively, and it was shown to inhibit the same enzyme from different sources, with high selectivity over the human homologue glutathione reductase (hGR). The most intriguing feature is represented by its chemotype, which is known to be able to cross the brain-blood barrier, particularly important in the treatment of the central nervous system phase of HAT. Simultaneously, screening of the 192 compounds contained in the LeishBox, a set of best antileishmanial compounds identified by a cell-based HTS performed by GlaxoSmithKline (GSK) over 1.8 million compounds (a HATBox and a ChagasBox were additionally built) (Peña et al., 2015), led to a list of seven compounds active against TR from L. infantum (Ilari et al., 2018); SPR experiments and docking predictions, together with a preliminary model of the crystal structure of TR in complex with compound A1/7, assessed the competitive fashion of the inhibition. A1/7 is among the most potent and selective inhibitors identified in the series and is contained also in the HATBox and ChagasBox, setting the basis for a broad-spectrum drug development. For this reason, it has been used as a scaffold for the synthesis of twelve derivatives (in collaboration with the medicinal chemistry group of Prof. Giuseppe Campiani, University of Siena, Italy), which are being tested at this time; three out of twelve display a better and/or comparable affinity with respect to A1/7, providing important information regarding the chemical modifications to be applied to boost affinity, supported by a preliminary crystallographic model of the TR-A1/7 complex. Finally, preliminary crystallographic studies have been performed, in order to fulfil pre-requirements needed for an FBS, to be performed in the near future at the Xchem-Screening platform, at Diamond Light Source (Didcot, UK). Reproducible high-diffracting, DMSO-resistant and ligand accessible crystals have been obtained by setting up an automated protocol.
Future steps are those typical of the hit optimization round; the information so far collected will be used for intense SAR studies in order to obtain more potent and specific inhibitors. Efforts will be carried out in order to acquire structural information via X-ray crystallography, to proceed with a structure-based campaign. FBS results will help in designing new scaffolds and pharmacophores, facilitating the discovery of a single inhibitor for this family-specific and highly conserved target.
References
Ilari, A., Genovese, I., Fiorillo, F., Battista, T., De Ionna, I., Fiorillo, A., & Colotti, G. (2018). Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors. Molecular Pharmaceutics, 15(8), 3069–3078.
Peña, I., Pilar Manzano, M., Cantizani, J., Kessler, A., Alonso-Padilla, J., Bardera, A. I., Alvarez, E., Colmenarejo, G., Cotillo, I., Roquero, I., De Dios-Anton, F., Barroso, V., Rodriguez, A., Gray, D. W., Navarro, M., Kumar, V., Sherstnev, A., Drewry, D. H., Brown, J. R., ... Julio Martin, J. (2015). New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: An open resource. Scientific Reports, 5.
Turcano, L., Battista, T., De Haro, E. T., Missineo, A., Alli, C., Paonessa, G., Colotti, G., Harper, S., Fiorilloid, A., Ilari, A., & Bresciani, A. (2020). Spiro-containing derivatives show antiparasitic activity against trypanosoma brucei through inhibition of the trypanothione reductase enzyme. PLoS Neglected Tropical Diseases, 14(5), 1–17
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Sulmona, S. Francesco della Scarpa; Goriano Sicoli, S. Gemma
No full textNell’ambito di una delle prime indagini sui danni al patrimonio storico-architettonico dell’Abruzzo a seguito del terremoto del 6 aprile 2009, sono stati presi in esame due edifici chiesastici. Nel caso di S. Francesco della Scarpa a Sulmona, la principale chiesa francescana della regione, si sintetizzano le principali fasi costruttive e la soluzione finale con l’originale fusione tra impianto centrale e longitudinale. Si rileva come l’edificio, pur non manifestando lesioni e crolli evidenti, sia staticamente compromesso, anche a causa della successione di interventi edilizi, e se ne raccomanda l’inserimento fra i monumenti da restaurare con priorità elevata. La chiesa di S. Gemma a Goriano Sicoli, piccolo centro della valle Subequana, è frutto di una radicale ricostruzione settecentesca completata agli inizi del XIX secolo. Il terremoto del 2009 ha provocato la parziale rotazione della facciata e danni ingentissimi ai pilastri e all’elevato dell’edificio, rendendone urgente il restauro
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
LA CHIESA DI S. GEMMA A GORIANO SICOLI (AQ): MECCANISMI DI DANNO E ANALISI DI SISMORESISTENZA
No full textAnalizzando lo stato di danno manifestato nella Chiesa di S. Gemma a Goriano Sicoli (AQ) a seguito dell’evento sismico del 6 aprile 2009 in Abruzzo, si stabilisce una correlazione fra l’input sismico che la chiesa ha subito e l’effettiva resistenza dei vari macroelementi costituenti la struttura. L’analisi dei meccanismi di danno attivati viene svolta tramite analisi cinematiche lineari e non lineari e modellazioni FEM. In questo modo, oltre ad analizzare il comportamento sismico del manufatto, si mettono in evidenza alcune peculiarità dell’evento sismico aquilano e gli effetti di amplificazione locale del sito di Goriano Sicoli. A conclusione vengono proposti ed analizzati alcuni interventi di riparazione e consolidamento dei vari elementi danneggiati dal sisma
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
- …
