1,720,973 research outputs found
INVESTIGATING THE NR2F2 STRUCTURE FOR DRUG REPURPOSING
No full textNuclear receptors (NRs) are transcription factors which play a crucial role in regulating various physiological and developmental processes. Within this superfamily, NR2Fs, also known as Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF), is a family of nuclear orphan receptors, due to the lack of endogenous ligands. The NR2Fs are composed of three members: NR2F1 (COUP-TFI), NR2F2 (COUP-TFII) and NR2F6 (COUP-TFIII). Structurally, the two most important regions, but independently from each other, of NRs are the DNA binding domain (DBD) and ligand binding domain (LBD) which is homologous between all three family members. The variable N-terminal is less conserved, the C-terminal region does not exist in all receptors, and its function is not well understood. Due to their central role in cell growth, they are promising candidates as novel therapeutic targets for cancer therapy [T Sajinovic, G Baier. doi: 10.31083/j.fbl2801013]. In this context, we performed a computational analysis on the X-ray crystal structure of the human NR2F2 ligand binding domain (PDBID: 3CJW) to comprehend the potential hotspot binding sites and predict their druggability. The two identified binding sites (Figure) were then used in a virtual screening protocol, including pharmacophore models and docking studies, of large libraries such as Drugbank, FDA, and commercial libraries for drug repurposing. The results of this investigation will be reported and discussed
A comprehensive computational analysis of NR2F2/6 receptors for drug repurposing
No full textNuclear Receptors (ORFs) are a small family of transcription factors (15 members)
playing a crucial role in regulating various physiological and developmental processes.
Within this superfamily, NR2Fs, also known as Chicken Ovalbumin Upstream Promoter
Transcription Factor (COUP-TF), is a family of nuclear orphan receptors, due to the lack of
endogenous ligands. The NR2Fs are composed of three members: NR2F1 (COUP-TFI, EAR-
3), NR2F2 (COUP-TFII, ARP-1) and NR2F6 (COUP-TFIII, EAR-2). Due to the pivotal functions
of NR2Fs in cell growth, they are regarded as promising candidates for the development
of novel therapeutic targets in cancer treatment [1]. In the context of the PNRR project,
"HEAL ITALIA", a comprehensive computational analysis was conducted on the X-ray
crystal structures of the human ligand binding domain of NR2F2 (PDB ID: 3CJW) and the
NR2F6 (PDB ID: 8C5L). To date, only compound CIA1 has been identified as an inhibitor of
NR2F2 in prostate cancer cell lines (IC50 1.2-7.6 μM). To this aim, the ligand binding
domain was mapped identifying potential binding sites, designated as site 1 and site 2.
Followed by classic docking with CIA1, molecular dynamics (MD), Binding Pose
Metadynamics (BPMD), and Molecular Mechanics-Generalized Born Surface Area
continuum solvation (MM-GBSA) were conducted to assess the stability of the complexes
NR2F2-CIA in the two sites. For NR2F6 no inhibitor has been identified in the literature.
Potential hotspot binding sites were identified and their potential for drug use was
predicted. Subsequently, the identified binding sites for NR2F2 and NR2F6 were then
used to perform a virtual screening protocol involving pharmacophore models and
docking studies on extensive libraries, such as Drugbank, FDA and commercial libraries
for drug repurposing
Non-covalent immunoproteasome inhibitors: virtual screening and in vitro test on β1i /β5i subunits
No full textImmunoproteasome inhibition is a challenging strategy for the treatment of hematological malignancies, autoimmune and inflammatory diseases [1,2]. The search for non-covalent inhibitors of the immunoproteasome β1i/β5i catalytic subunits could be a new strategy to avoid the drawbacks of the known covalent inhibitors. Here, we report the biological evaluation of thirty-four compounds selected from commercial libraries. A virtual screening strategy including a dynamic pharmacophore modeling approach onto the β1i subunit and a pharmacophore/docking approach onto the β5i subunit aided the identification of these hits [3]. Compound 3 is the most active onto β1i subunit with Ki = 11.84±1.63 μM, compound 17 showed Ki = 12.50±0.77 μM onto β5i subunit. Compound 2 showed inhibitory activity on both subunits (Ki = 12.53±0.18 Ki = 31.95±0.81 onto β1i subunit and β5i subunit, respectively). The hit compounds identified represent an interesting starting point for further optimization
Uno studio comparativo in silico sui possibili target di Ataluren e analoghi farmaci promotori di readthrough di codoni di stop prematuri
Full text linkE’ noto in letteratura che Ataluren (acido 5-(fluorofenil)-1,2,4-ossadiazolil-benzoico) sia in grado di sopprimere le mutazioni non senso favorendo il readthrough dei codoni di stop prematuri, anche se il suo meccanismo di azione non risulta ancora chiaro. La probabile interazione tra Ataluren e CTFR-mRNA è stata precedentemente studiata mediante dinamica molecolare. In questo studio1, abbiamo esteso il modeling del probabile meccanismo di azione di Ataluren mediante approcci computazionali completementari, quali Induced Fit Docking (IFD), Quantum Polarized Ligand Docking (QPLD), metodi MM-GBSA e mutagenesi computazionale. Oltre a considerare il CTFR-mRNA, sono stati presi in considerazione altri target implicati nel processo di traduzione, quali la subunità 16S dell’rRNA batterico e la subunità 18S dell’rRNA eucariotico, che sono target comprovati di molti aminoglicosidi noti per la loro capacità di sopprimere l’attività di correzione svolta normalmente dal ribosoma; il fattore di rilascio eucariotico eRF1, per valutare la potenziale influenza di Ataluren sulla fine del processo di traduzione. Inoltre, è stato effettuato un confronto tra Ataluren, un suo nuovo promettente analogo NV2445 (acido 4-(5-(o-tolil)-1,3,4-ossadiazol-2-il)benzoico)2 e una serie di antibiotici aminoglicosidici. I risultati hanno confermato che mRNA è il più probabile target per Ataluren e i suoi derivati. I calcoli di energia libera di legame effettuati in seguito alla mutagenesi computazionale, hanno mostrato che il legame tra Ataluren e il codone di stop prematuro è fortemente influenzato dalla presenza di nucleotidi ausiliari nell’intorno genico
Exploring the new non-covalent immunoproteasome inhibitors of β1i /β5i subunits: Virtual screening and in vitro test
No full textDesign of small molecules and identification of putative anticancer therapeutic targets via in silico tools
No full textComputational approaches are a key component in drug design and discovery workflows. Several computational tools have been implemented in the last years to help researchers save time and reduce costs. They can be used to identify a therapeutic target, understand ligand-protein and protein-protein interactions, and identify putative binding sites, even though their principal use remains the identification of hit compounds through ligand-based and structure-based virtual screening and optimizing lead compounds [1]. Here, in the context of the PNRR project "HEAL ITALIA", we present the computational workflows to identify new potential anticancer compounds. Ligand-based approaches will be discussed guiding our research for new active compounds together with advanced docking approaches, biased and unbiased molecular dynamics simulations. In vitro test confirmed the results of the computational approaches and paved the way for the hits optimizatio
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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