1,720,975 research outputs found
Multitarget Drug Design for Neurodegenerative Diseases
No full textThe quest for new pharmacological treatments of neurodegenerative diseases (NDs) still remains a priority for researchers and caregivers. Being inherently multifactorial, NDs benefited of the paradigm shift from “one-drug-one-target” to “one-drug-more-target” which is typical of the so-called multitarget approach, whose ultimate aim is that of providing a wider pharmacological spectrum to single molecular entities. A multitarget drug should encompass the basic molecular features necessary for an effective interaction with each desired biological target. In this respect, different drug design strategies, mostly inspired by ligand- based and target-based approaches, have been envisaged to achieve this goal. Indeed, huge efforts have been addressed in recent years to harmonically integrate the amount of different (bio)chemical information in the attempt to derive reliable predictive multitarget models. An overview of multitarget computational methods as well as of some successful applications to NDs will be the focus of this chapter
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
Accelerating drug discovery by early protein drug target prediction based on a multi-fingerprint similarity search †
No full textIn this continuing work, we have updated our recently proposed Multi-fingerprint Similarity Search algorithm (MuSSel) by enabling the generation of dominant ionized species at a physiological pH and the exploration of a larger data domain, which included more than half a million high-quality small molecules extracted from the latest release of ChEMBL (version 24.1, at the time of writing). Provided with a high biological assay confidence score, these selected compounds explored up to 2822 protein drug targets. To improve the data accuracy, samples marked as prodrugs or with equivocal biological annotations were not considered. Notably, MuSSel performances were overall improved by using an object-relational database management system based on PostgreSQL. In order to challenge the real effectiveness of MuSSel in predicting relevant therapeutic drug targets, we analyzed a pool of 36 external bioactive compounds published in the Journal of Medicinal Chemistry from October to December 2018. This study demonstrates that the use of highly curated chemical and biological experimental data on one side, and a powerful multifingerprint search algorithm on the other, can be of the utmost importance in addressing the fate of newly conceived small molecules, by strongly reducing the attrition of early phases of drug discovery programs
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
Targeting protein-protein interactions with low molecular weight and short peptide modulators: insights on disease pathways and starting points for drug discovery
No full textIntroduction: Protein-protein interactions (PPIs) have been often considered undruggable targets although they are attractive for the discovery of new therapeutics. The spread of artificial intelligence and machine learning complemented with experimental methods is likely to change the perspectives of protein-protein modulator research. Noteworthy, some novel low molecular weight (LMW) and short peptide modulators of PPIs are already in clinical trials for the treatment of relevant diseases. Areas covered: This review focuses on the main molecular properties of protein-protein interfaces and on key concepts pertaining to the modulation of PPIs. The authors survey recently reported state-of-the-art methods dealing with the rational design of PPI modulators and highlight the role of several computer-based approaches. Expert opinion: Interfering specifically with large protein interfaces is still an open challenge. The initial concerns about the unfavorable physicochemical properties of many of these modulators are nowadays less acute with several molecules lying beyond the rule of 5, orally available and successful in clinical trials. As the cost of biologics interfering with PPIs is very high, it would seem reasonable to put more effort, both in academia and the private sectors, on actively developing novel low molecular weight compounds and short peptides to perform this task
Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to
Full text linkThe fusion oncoprotein Bcr-Abl is an aberrant tyrosine kinase responsible for chronic myeloid leukemia and acute lymphoblastic leukemia. The auto-inhibition regulatory module observed in the progenitor kinase c-Abl is lost in the aberrant Bcr-Abl, because of the lack of the N-myristoylated cap able to bind the myristoyl binding pocket also conserved in the Bcr-Abl kinase domain. A way to overcome the occurrence of resistance phenomena frequently observed for Bcr-Abl orthosteric drugs is the rational design of allosteric ligands approaching the so-called myristoyl binding pocket. The discovery of these allosteric inhibitors although very difficult and extremely challenging, represents a valuable option to minimize drug resistance, mostly due to the occurrence of mutations more frequently affecting orthosteric pockets, and to enhance target selectivity with lower off-target effects. In this perspective, we will elucidate at a molecular level the structural bases behind the Bcr-Abl allosteric control and will show how artificial intelligence can be effective to drive the automated de novo design towards off-patent regions of the chemical space
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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