1,720,984 research outputs found
Structural insights into the immune subversion of coronaviruses and identification of potent small molecule inhibitors using computational approaches
No full text학위논문(박사)--아주대학교 일반대학원 :분자과학기술학과,2020. 8CHAPTER 1 1
Introduction 1
1.1 Overview of Coronaviruses 2
1.2 Entry and replication of viruses 3
1.3 Potential therapeutic targets 6
CHAPTER 2 9
Methods 9
2.1 Protein modeling and interface analysis 10
2.2 Alanine scanning mutagenesis 10
2.3 Virtual screening and molecular docking 11
2.4 Molecular dynamic simulations 12
2.5 Principal component analysis 15
2.6 Free energy landscape 15
2.7 MMPBSA 16
2.8 Data analysis and visualization 17
CHAPTER 3 18
Results and Discussion 1 18
Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism 19
3.1 Summary 20
3.2 3D modeling of p4a-dsRNA complex and interface analyses 20
3.3 Identification of hotspot residues and their influence on p4a-dsRNA binding mechanism 23
3.4 Investigation of impact of hotspot residues on p4a-dsRNA complex through structural dynamics 24
3.5 Interactions analysis between p4a-dsRNA wild type complex and mutants 27
3.6 Dynamic motions of MERS-CoV p4a mutants 27
3.7 Transition of proteins from unfolded to native state 31
3.8 Binding free energy calculation 32
3.9 Discussion 33
CHAPTER 4 36
Results and Discussion 2 36
Discovery of potential inhibitors to block MERS-CoV evasion from the host immune system by targeting a non-structural accessory protein 37
4.1 Summary 38
4.2 Understanding of dynamic behavior and stability of p4a 38
4.3 Identification of potential compound to block p4a-dsRNA interaction 39
4.4 Identification of physicochemical and pharmacokinetic properties 45
4.5 Discussion 46
CHAPTER 5 48
Results and Discussion 3 48
Structural insights into the behavior of the catalytic site of SARS-CoV-2 main protease 49
5.1 Summary 50
5.2 Analysis of apo-3CL protease behavior via MD simulations 50
5.3 Dynamic behavior of 3CL protease with different ligands 52
5.4 The behavior of 3CL protease catalytic site in the presence of ligands 58
5.5 The binding energy of ligands toward 3CL protease 60
5.6 Discussion 61
Bibliography 64
Appendix 1 74
Appendix 2 75
Appendix 3 76DoctoralThe recent occurrence of COVID-19 pandemic causing fever, respiratory illness, and pneumonia, has drawn the attention across the globe and has been declared a global health emergency. Among humans, coronaviruses were not believed to be pathogenic until the severe acute respiratory syndrome (SARS) epidemic occurred in late 2002. Ten years later in 2012, a new coronavirus epidemic named as Middle East respiratory syndrome (MERS) emerged in Asian and Middle Eastern countries. Several studies have been published to understand the cell entry, replication, and protein structures of virus. The genomic organization of SARS and MERS is similar, comprising an enveloped, positive-sense, single-stranded RNA genome that translates into various structural and non-structural proteins (nsps). After viral entry into the host cell, virus releases its RNA into the cytoplasm where it is translated into polyproteins pp1a and pp1ab. These polyproteins are cleaved by proteases that produce 16 nsps. The viral genome is translated, replicated, and assembled in the cytoplasm which is then released via exocytosis.
To combat with the coronavirus diseases, it is important to block viral infection or replication. Therefore, two potential target proteins were selected for the drug development. The first target is an accessory protein 4a of MERS-CoV which has been proved through in vitro and in vivo studies that it is involved in inhibition of IFN production which influences the viral pathogenicity. 3D structure of protein 4a was modeled followed by structural validation and computational alanine mutagenesis. Residues N8, K27, W45, K63, and K67 were selected based on the dStability and dAffinity values. The mutant and wild type complexes were simulated for 200 ns each. The MD simulation results revealed that K27, W45, K63, and K67 are key residues that play crucial role in RNA binding. Thus, suggesting that blocking these residual interactions could destabilize the 4a-RNA complex. Furthermore, considering these residues a part of binding site, virtual screening of
antiviral as well as druglike and leadlike compounds from ZINC database is conducted using the most stable confirmation extracted from MD simulations. The ten compounds from both datasets were selected based on binding affinity scores and their binding pose. The interactions were analyzed in detail along with the free binding energy calculations. Most of the selected compounds possess antiviral properties. These compounds can be tested through in vitro and in vivo experiments.
The 3CL protease is another potential target due to its proteolytic activity that cleaves the polyprotein. Many drugs have been repositioned, and a few ligands are cocrystalized with SARS-CoV-2 3CL protease. The flexibility of the catalytic site leads to the conformational changes that influences the ligand binding. Thus, it is necessary to probe the flexibility and rigidity of protein’s active site. 100 ns MD simulations were performed for apo form of 3CL protease and its complexes with different cocrystalized ligands. The trajectory analysis and binding free energy calculation revealed that the ligand that can break the catalytic dyad bond in the active site would be a potential candidate to block the proteolytic activity. The alpha-keto group present in the inhibitor of 6LU7 make strong bonds with both residues Cys and His of catalytic dyad. Therefore, addition of such chemical groups that break the bond between Cys and His would be important to block the functional 3CL protease.
Conclusively, both target proteins 4a and 3CL protease are important for viral pathogenicity and replication, respectively. Therefore, understanding of structure dynamics and insights into the binding site is crucial for development of an efficient drug molecule. 3CL protease is structurally and functionally conserved protein among all three coronaviruses. Thus, targeting this protein would be a hope to combat all coronavirus diseases
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
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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