1,720,961 research outputs found
Molecular Interactions of Cobimetinib and Vemurafenib with Human Serum Albumin: a Comparative Biophysical and Computational Analysis
No full textThe combined use of BRAF and MEK inhibitors has transformed the management of BRAFV600-mutated melanoma, yet the pharmacokinetic interplay between cobimetinib (COB) and vemurafenib (VEM) remains incompletely understood. Here, we investigated the binding interactions of COB and VEM with human serum albumin (HSA) using a multidisciplinary approach combining fluorescence spectroscopy, isothermal titration calorimetry, circular dichroism, and molecular simulations. Both inhibitors form stable complexes with HSA, predominantly at Sudlow’s site II, driven by different interactions pattern. Thermodynamic and kinetic analyses revealed distinct binding behaviors: COB binding is entropy-driven (ΔH = +5.88 ± 0.32 kJ/mol; ΔG = −24.19 kJ/mol), with a dissociation constant (Kd) of 58.2 μM and a residence time of 1.45 s, indicating rapid and dynamic engagement. In contrast, VEM displays a more enthalpy-favored profile (ΔH = −22.05 ± 0.31 kJ/mol), stronger binding affinity (Kd≈ 4.8 μM), and a longer residence time of 18.5 s. Stoichiometry for both ligands is approximately 1:1, as determined by ITC. Structural analyses revealed subtle conformational alterations in HSA upon ligand binding, while enzymatic assays demonstrated that both COB and VEM competitively inhibit HSA’s esterase-like activity. These findings highlight distinct binding kinetics and functional consequences for each drug, offering critical insights into their pharmacokinetic behavior during combination therapy and providing a foundation for optimizing systemic exposure and therapeutic efficacy
Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study
Full text link: Drug binding to human serum albumin (HSA) significantly affects in vivo drug transport and biological activity. To gain insight into the binding mechanism of the two B-Raf tyrosine kinase inhibitors dabrafenib and vemurafenib to HSA, in this work, we adopted a combined strategy based on fluorescence spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and molecular simulations. Both anticancer drugs are found to bind spontaneously and with a 1:1 stoichiometry within the same binding pocket, located in Sudlow's site II (subdomain IIIA) of the protein with comparable affinity and without substantially perturbing the protein secondary structure. However, the nature of each drug-protein interactions is distinct: whereas the formation of the dabrafenib/HSA complex is more entropically driven, the formation of the alternative vemurafenib/HSA assembly is prevalently enthalpic in nature. Kinetic analysis also indicates that the association rate is similar for the two drugs, whereas the residence time of vemurafenib within the HSA binding pocket is somewhat higher than that determined for the alternative B-Raf inhibitor
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
Beyond the Veil: Free Energy Profiles and Partition Coefficients for Antimelanoma Drugs in Self-Assembled Nanomicelles via COSMOmic and Atomistic Molecular Dynamics Simulations
No full textThis study investigates the encapsulation efficiency (EE) and molecular interactions between amphiphilic dendrimer nanomicelles (AD NMs) and six BRAF inhibitors (BRAFis) used in melanoma treatment: dabrafenib (DAB), vemurafenib (VEM), ponatinib (PON), AZ 628 (AZ), PLX8394 (PLX) and encorafenib (ENC). Experimental determination of EE coupled with computational methods, including molecular dynamics and COSMOmic simulations, was employed to explore the drug encapsulation behavior. The results indicate efficient encapsulation of all BRAF inhibitors by AD NMs with different EE values. DAB, ENC, and PLX exhibit a higher EE (~75%), while VEM, AZ, and PON show slightly lower encapsulation efficiency (~60%). Molecular dynamics and COSMOmic simulations identify three binding positions (POS 1, POS 2, POS 3) within the nanocarrier, revealing preferential sites for each BRAFi. Hydrophobic interactions dominate in POS 1, while electrostatic forces play a crucial role in POS 2 and POS 3. Partition coefficient (logK) analysis shows that DAB, ENC, and PLX have higher affinity for the nanocarrier. This study combines experimental and computational insights to improve understanding of BRAFi-AD NM interactions, essential for optimizing drug delivery systems and advancing the development of melanoma treatmen
Molecular insights into the binding of human serum albumin to charged dendritic nanomicelles: A synergistic experimental and in silico approach
No full textUnderstanding the interaction between dendritic nanostructures and plasma proteins is critical for optimizing their in vivo behavior and biocompatibility. In this study, we investigate the binding of human serum albumin (HSA) to a set of amphiphilic poly(amidoamine) dendrimers, both as individual monomers and as self-assembled charged nanomicelles (1@-A, 1@-TA, and 1@-COOH). A comprehensive set of techniques, including fluorescence spectroscopy, circular dichroism, isothermal titration calorimetry, dynamic light scattering, and atomistic molecular dynamics simulations, was employed to assess binding affinity, conformational effects, and complex stoichiometry resulting from the interactions between the serum protein and the dendritic nanostructures. Isothermal titration calorimetry quantified stronger HSA binding for nanomicelles (Kd = 1.15 ± 0.64 μM for 1@-A; 4.29 ± 0.57 μM for 1@-COOH; 8.10 ± 0.11 μM for 1@-TA) relative to monomers (Kd = 112 ± 11, 89 ± 21, and 104 ± 18 μM for 1-A, 1-TA, and 1-COOH, respectively). The thermodynamic signatures differed markedly: nanomicelles exhibited favorable enthalpy (ΔH = −4.07 ± 0.05 to −6.53 ± 0.04 kcal/mol) with modest entropic contributions (−TΔS = −4.09 ± 0.40 to −0.80 ± 0.04 kcal/mol), whereas monomers were entropy-driven (ΔH = +2.88 ± 0.14 to +3.12 ± 0.10 kcal/mol; −TΔS = −8.51 ± 0.21 to −8.41 ± 0.23). Spectroscopic analyses indicated that HSA retained its secondary and tertiary structures upon interaction and confirmed the formation of stable protein–nanomicelle complexes. Computational modeling revealed distinct interaction patterns at the HSA–nanomicelle interface. Together, these findings demonstrate how the structural and surface properties of dendritic nanomicelles can modulate their interaction with proteins, offering valuable insights for future design strategies. Given that the formation of a soft protein corona, especially around micelles, plays a pivotal role in protein–nanomaterial interactions, the results presented here may constitute a key step toward the rational design of next-generation nanomedicine platforms
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
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