1,720,966 research outputs found
Sigma-1 receptor antagonists: promising players in fighting neuropathic pain
No full textSigma-1 receptors (S1Rs) are strongly correlated to neuropathic pain (NP), since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effects. In the recent patent landscape, S1R antagonists endowed with nanomolar S1Rs affinity emerged as potent antinociceptive agents. So far, three patented compounds have been proposed for counteracting NP. Particularly PV 752 and AV1066, disclosed by the University of Pavia (Italy) and Anavex, respectively, showed good analgesic activity in preclinical studies. Moreover, E 52862 developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans
Urea-based anticancer agents. Exploring 100-years of research with an eye to the future
No full textSuramin was the first urea-based drug to be approved in clinic, and in the following century a number of milestone drugs based on this scaffold were developed. Indeed, urea soon became a privileged scaffold in medicinal chemistry for its capability to establish a peculiar network of drug−target interactions, for its physicochemical properties that are useful for tuning the druggability of the new chemical entities, and for its structural and synthetic versatility that opened the door to numerous drug design possibilities. In this review, we highlight the relevance of the urea moiety in the medicinal chemistry scenario of anticancer drugs with a special focus on the kinase inhibitors for which this scaffold represented and still represents a pivotal pharmacophoric feature. A general outlook on the approved drugs, recent patents, and current research in this field is herein provided, and the role of the urea moiety in the drug discovery process is discussed form a medicinal chemistry standpoint. We believe that the present review can benefit both academia and pharmaceutical companies’ medicinal chemists to prompt research towards new urea derivatives as anticancer agents
Biophysical Assays for Investigating Modulators of Macromolecular Complexes: An Overview
No full text: Drug discovery is a lengthy and intricate process, and in its early stage, crucial steps are the selection of the therapeutic target and the identification of novel ligands. Most targets are dysregulated in pathogenic cells; typically, their activation or deactivation leads to the desired effect, while in other cases, interfering with the target-natural binder complex achieves the therapeutic results. Biophysical assays are a suitable strategy for finding new ligands or interferent agents, being able to evaluate ligand-protein interactions and assessing the effect of small molecules (SMols) on macromolecular complexes. This mini-review provides a detailed analysis of widely used biophysical methods, including fluorescence-based approaches, circular dichroism, isothermal titration calorimetry, microscale thermophoresis, and NMR spectroscopy. After a brief description of the methodologies, examples of interaction and competition experiments are described, together with an analysis of the advantages and disadvantages of each technique. This mini-review provides an overview of the most relevant biophysical technologies that can help in identifying SMols able not only to bind proteins but also to interfere with macromolecular complexes
New LsrK Ligands as AI-2 Quorum Sensing Interfering Compounds against Biofilm Formation
No full textAntimicrobial resistance (AMR) represents a critical global health crisis. An innovative strategy to deal with AMR is to interfere with biofilm formation and bacterial quorum sensing (QS). In this study, newly designed autoinducer-2 (AI-2)-inspired compounds in targeting biofilm-associated infections were evaluated for their ability to inhibit biofilm formation in Staphylococcus aureus and Pseudomonas aeruginosa. The most effective compounds, 5d, 5e, and 7b, exhibited potent antibiofilm activity with minimal inhibitory concentrations in the low microgram per mL range. Detailed biological assays confirmed that the antibiofilm activity was primarily driven through AI-2 QS inhibition rather than direct antimicrobial effects. The combination of different spectroscopic techniques, such as differential scanning fluorimetry, intrinsic tryptophan fluorescence, circular dichroism, and nuclear magnetic resonance, elucidated the binding between the compounds and the LsrK enzyme, a key player in AI-2 mediated QS. Our findings highlight the potential of these novel QS inhibitors as promising therapeutic agents against biofilm-associated infections
Tackling Antimicrobial Resistance with Small Molecules Targeting LsrK: Challenges and Opportunities
No full textAntimicrobial resistance (AMR) is a growing threat with severe health and economic consequences. The available antibiotics are losing efficacy, and the hunt for alternative strategies is a priority. Quorum sensing (QS) controls biofilm and virulence factors production. Thus, the quenching of QS to prevent pathogenicity and to increase bacterial susceptibility to antibiotics is an appealing therapeutic strategy. The phosphorylation of autoinducer-2 (a mediator in QS) by LsrK is a crucial step in triggering the QS cascade. Thus, LsrK represents a valuable target in fighting AMR. Few LsrK inhibitors have been reported so far, allowing ample room for further exploration. This perspective aims to provide a comprehensive analysis of the current knowledge about the structural and biological properties of LsrK and the state-of-the-art technology for LsrK inhibitor design. We elaborate on the challenges in developing novel LsrK inhibitors and point out promising avenues for further research
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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