1,720,956 research outputs found
Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors
No full textThe thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design
Biochemical characterisation of human KifC1 and Eg5, two potential targets for drug development in cancer chemotherapy
Get PDFKinesins are ATP-dependent molecular motors that mostly travel unidirectionally along microtubules (MTs) to fulfil their roles in intracellular transport or cell division. Those involved in cell division, known as mitotic kinesins have been implicated in a variety of cancers. As they are crucial for cell division, certain mitotic kinesins such as Eg5 and KifC1 have been considered for their potential as novel drug targets. This is with the hope that these drugs will have fewer toxic side effects than conventional cancer therapies using taxanes and vinca alkaloids. Today, several inhibitors targeting Eg5 have entered Phase I, II and III clinical trials either as monotherapies or in combination with other drugs. As new members are continually being validated, KifC1 is also becoming increasingly important as a potential new target. My PhD thesis focuses on the characterisation of human mitotic kinesins KifC1 and Eg5, two potential targets for drug development in cancer chemotherapy. The first part of this thesis (chapter 3) covers the investigation of KifC1. Firstly, the development and optimisation of the protocols for the expression and purification of several KifC1 constructs covering full-length KifC1 is presented. Then, secondary structure and biophysical characterisation of each KifC1 domain is examined. Furthermore, biochemical characterisation of KifC1 is described and the kinetic properties of each construct in relation to the biophysical data such as oligomeric state is discussed. After this, attempts to crystallise the KifC1 motor domain are described. Finally, inhibitor screening of 15,000 small molecules for KifC1-specific hits are reported. The results provide a basis for future characterisation of KifC1. The second part of this thesis (chapter 4) involves the investigation of K858, a novel inhibitor of Eg5 bearing the 1,3,4-thiadiazole scaffold, an important core moiety in many clinical drug candidates targeting a variety of diseases. Biochemical and biophysical characterisation of K858 binding to Eg5 is reported. 1.8 Å resolution crystal structure of the Eg5-K858 complex (PDB ID: 6G6Y) is presented, providing the first structural evidence of how the thiadiazole containing scaffolds ARRY-520 is so successful in advancing into phase III clinical trials. Finally, structure-activity relationship (SAR) study of 22 K858 analogues is reported
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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