1,720,999 research outputs found
A Common Reference Framework for Analyzing/Comparing Proteins and Ligands. Fingerprints for Ligands and Proteins (FLAP): Theory and Application
No full textBioGPS: Navigating biological space to predict polypharmacology, off-targeting, and selectivity
No full textThe structural comparison of protein binding sites is increasingly important in drug design; identifying structurally similar sites can be useful for techniques such as drug repurposing, and also in a polypharmacological approach to deliberately affect multiple targets in a disease pathway, or to explain unwanted off-target effects. Once similar sites are identified, identifying local differences can aid in the design of selectivity. Such an approach moves away from the classical “one target one drug” approach and toward a wider systems biology paradigm. Here, we report a semiautomated approach, called BioGPS, that is based on the software FLAP which combines GRID Molecular Interactions Fields (MIFs) and pharmacophoric fingerprints. BioGPS comprises the automatic preparation of protein structure data, identification of binding sites, and subsequent comparison by aligning the sites and directly comparing the MIFs. Chemometric approaches are included to reduce the complexity of the resulting data on large datasets, enabling focus on the most relevant information. Individual site similarities can be analyzed in terms of their Pharmacophoric Interaction Field (PIF) similarity, and importantly the differences in their PIFs can be extracted. Here we describe the BioGPS approach, and demonstrate its applicability to rationalize off-target effects (ERα and SERCA), to classify protein families and explain polypharmacology (ABL1 kinase and NQO2), and to rationalize selectivity between subfamilies (MAP kinases p38α/ERK2 and PPARδ/PPARγ). The examples shown demonstrate a significant validation of the method and illustrate the effectiveness of the approach. Proteins 2015; 83:517–532. © 2015 Wiley Periodicals, Inc
Comparison of ligand-based and structure-based 3D-QSAR approaches: a case study on (aryl-)bridged 2-aminobenzonitriles inhibiting HIV-1 reverse transcriptase
No full textLigand- (GRIND) and structure-based (GLUE/GRIND) 3D-QSAR approaches were compared for 55 (aryl-)bridged 2-aminobenzonitriles inhibiting HIV-1 reverse transcriptase (HIV-1 RT). The ligand-based model was built from conformers selected by in vacuo minimization. The available X-ray structure of 3v in complex with HIV-1 RT allowed comparative structure-based calculations using the new docking software GLUE for conformer selection. Both models were validated via statistics and via virtual receptor sites (VRS) considering pharmacophoric regions and mutual distances, which were also compared with experimental evidence. The statistics show slight superiority of the structure-based approach in terms of fitting and prediction. By encoding relevant molecular interaction fields (MIF) into pharmacophoric regions, 10 such regions were derived from both models; they all fit the real receptor except HBD2. Also mutual distances highly agree between the real site and both VRS. Although distances from the structure-based approach are closer to the real receptor, present data prove the validity of the ligand-based GRIND approach
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
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