1,720,959 research outputs found
Computational Methods in the Discovery and Design of BACE-1 Inhibitors.
No full textBACE-1 is a membrane associated aspartyl protease and is one of the enzymes responsible for the hydrolysis of the amyloid precursor protein. Due to its central role in the generation of the amyloid-β peptide, it is considered as a primary drug target for Alzheimer's disease. BACE-1 has been the focus of many drug discovery programs aimed at identifying inhibitors that effectively block this enzyme and trigger the sought therapeutic effects. Thanks to the availability of a large number of crystal structures of the catalytic domain of this enzyme, computational methods, ranging from molecular dynamics simulations, quantum mechanical calculations and ligand docking, have played a fundamental role in almost every hit discovery and hit optimization campaign performed on this target. The present article reviews the latest computational modeling and drug discovery efforts that have been carried out on this target
Computational Methods in the Discovery and Design of BACE-1 Inhibitors
No full textBACE-1 is a membrane associated aspartyl protease and is one of the enzymes responsible for the hydrolysis of the amyloid precursor protein. Due to its central role in the generation of the amyloid-beta peptide, it is considered as a primary drug target for Alzheimer's disease. BACE-1 has been the focus of many drug discovery programs aimed at identifying inhibitors that effectively block this enzyme and trigger the sought therapeutic effects. Thanks to the availability of a large number of crystal structures of the catalytic domain of this enzyme, computational methods, ranging from molecular dynamics simulations, quantum mechanical calculations and ligand docking, have played a fundamental role in almost every hit discovery and hit optimization campaign performed on this target. The present article reviews the latest computational modeling and drug discovery efforts that have been carried out on this target
Combining Dyad Protonation and Active Site Plasticity in BACE-1 Structure-Based Drug Design
No full textThe ability of the BACE-1 catalytic dyad to
adopt multiple protonation states and the conformational
flexibility of the active site have hampered the reliability of
computational screening campaigns carried out on this
drug target for Alzheimer’s disease. Here, we propose a
protocol that, for the first time, combining quantum
mechanical calculations, molecular dynamics, and conformational
ensemble virtual ligand screening addresses
these issues simultaneously. The encouraging results
prefigure this approach as a valuable tool for future drug
discovery campaigns
Combining Dyad Protonation and Active Site Plasticity in BACE-1 Structure-Based Drug Design
No full textThe ability of the BACE-1 catalytic dyad to adopt multiple protonation states and the conformational flexibility of the active site have hampered the reliability of computational screening campaigns carried out on this drug target for Alzheimer's disease. Here, we propose a protocol that, for the first time, combining quantum mechanical calculations, molecular dynamics, and conformational ensemble virtual ligand screening addresses these issues simultaneously. The encouraging results prefigure this approach as a valuable tool for future drug discovery campaigns
Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments
No full textIn this study, we report on a virtual ligand screening protocol optimized to identify fragments endowed with activity at multiple targets. Thanks to this protocol, we were able to identify a fragment that displays activity in the low-micromolar range at both beta-secretase 1 (BACE-1) and glycogen synthase kinase 3 beta (GSK-3 beta). These two structurally and physiologically unrelated enzymes likely contribute, through different pathways, to the onset of Alzheimer's disease (AD). Therefore, their simultaneous inhibition holds great potential in exerting a profound effect on AD. In perspective, the strategy outlined herein can be adapted to other target combinations
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
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
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
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