1,721,005 research outputs found
Discovery of Allosteric Inhibition of Human ATP-Citrate Lyase
No full textATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. Wei and colleagues (published online in Nature April 3, 2019) now report the full structure of human ACLY in complex with NDI-091143, revealing an appealing allosteric inhibition mechanism for this compound
Application of MM-PBSA methods in virtual screening
Full text linkComputer-aided drug design techniques are today largely applied in medicinal chemistry. In particular, receptor-based virtual screening (VS) studies, in which molecular docking represents the gold standard in silico approach, constitute a powerful strategy for identifying novel hit compounds active against the desired target receptor. Nevertheless, the need for improving the ability of docking in discriminating true active ligands from inactive compounds, thus boosting VS hit rates, is still pressing. In this context, the use of binding free energy evaluation approaches can represent a profitable tool for rescoring ligand-protein complexes predicted by docking based on more reliable estimations of ligand-protein binding affinities than those obtained with simple scoring functions. In the present review, we focused our attention on the Molecular Mechanics-Poisson Boltzman Surface Area (MM-PBSA) method for the calculation of binding free energies and its application in VS studies. We provided examples of successful applications of this method in VS campaigns and evaluation studies in which the reliability of this approach has been assessed, thus providing useful guidelines for employing this approach in VS
Identification of a Possible Endocannabinoid-Mediated Mechanism of Action of Cetylated Fatty Acids
No full textSome musculoskeletal disorders, including osteoarthritis; arthrosis; post-traumatic injuries; and other inflammatory tendon, joint and muscular afflictions, still represent unmet medical needs. Cetylated fatty acids (CFAs) are key components of widely distributed over-the-counter products, especially for topical use, which are intended to reduce symptoms associated with these conditions. Nevertheless, the mechanism of action of CFAs’ analgesic and anti-inflammatory properties has not yet been clearly established. Endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), are known to produce analgesic and anti-inflammatory effects. These compounds undergo physiological inactivation operated by several enzymes, including monoacylglycerol lipase (MAGL). We herein demonstrate for the first time that the therapeutic effects of CFAs may be attributable, at least in part, to their MAGL inhibition activities, which induce a local increase in analgesic/anti-inflammatory endocannabinoids in close proximity to the site of administration. These findings pave the way for the development of new potent local analgesic agents, whose action is based on an indirect cannabinoid effect
α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases
Full text linkMuch of the experimental evidence in the literature has linked altered lipid metabolism to severe diseases such as cancer, obesity, cardiovascular pathologies, diabetes, and neurodegenerative diseases. Therefore, targeting key effectors of the dysregulated lipid metabolism may represent an effective strategy to counteract these pathological conditions. In this context, α/β-hydrolase domain (ABHD) enzymes represent an important and diversified family of proteins, which are involved in the complex environment of lipid signaling, metabolism, and regulation. Moreover, some members of the ABHD family play an important role in the endocannabinoid system, being designated to terminate the signaling of the key endocannabinoid regulator 2-arachidonoylglycerol. This Perspective summarizes the research progress in the development of ABHD inhibitors and modulators: design strategies, structure-activity relationships, action mechanisms, and biological studies of the main ABHD ligands will be highlighted
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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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