1,720,965 research outputs found
Treatment of Complex Regional Pain Syndrome (Crps): New Perspectives in the Use of Sulfonamides as Modulators of P2x Receptors
Full text linkSulfonamide moiety as "molecular chimera" in the design of new drugs
No full textThe -SO2NH- group is of great significance in modern pharmaceutical use since in sulfa-drugs it is possible to introduce easily chemical modifications, and even small changes may lead to an improved version of an already existing drug
Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects
Full text linkBy controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells. In recent decades, by coupling in silico and experimental methods, several natural products have been characterized to exert antioxidant effects by targeting the KEAP1/NRF2 pathway. In this review article, we analyze several natural products that were investigated experimentally and in silico for their ability to modulate KEAP1/NRF2 by non-covalent and covalent mechanisms. These latter represent the two main sections of this article. For each class of inhibitors, we reviewed their antioxidant effects and potential therapeutic applications, and where possible, we analyzed the structure-activity relationship (SAR). Moreover, the main computational techniques used for the most promising identified compounds are detailed in this survey, providing an updated view on the development of natural products as antioxidant agents
Exploring the non-covalent ligand-binding mechanism on immunoproteasome by enhanced Molecular Dynamics
No full textSelective inhibition of immunoproteasome is a valuable strategy to treat autoimmune and
inflammatory diseases, and hematologic malignancies. In particular, non-covalent inhibition
is strongly desirable because it is free of the drawbacks and side effects associated with
covalent inhibition. Recently, a new series of amide derivatives with Ki values in the low/submicromolar ranges toward the β1i subunit have been identified as non-covalent inhibitors
1
. We
investigated the binding mechanism of the most potent and selective inhibitor (1) to elucidate
the steps from the ligand entrance into the binding pocket to the ligand-induced
conformational changes. We carried out a total of 400ns of MD-binding analysis, followed by
200ns of plain MD. The trajectories clustering allowed identifying three representative poses
evidencing new key interactions with Phe31 and Lys33 together to a flipped orientation of a
representative pose. Further, Binding pose metadynamics (BPMD) studies have been performed
to evaluate the binding affinity, comparing
(1) with other four inhibitors of β1i subunit (2, 3, 4, and 5). Results are consistent with
experimental values of inhibition, confirming (1) as a lead compound of this series. The
adopted methods provided a full dynamic description of the binding events and the information
obtained could be exploited for the rational design of new and more active inhibitor
Indicaxanthin, a multi-target natural compound from Opuntia ficus-indica fruit: From its poly-pharmacological effects to biochemical mechanisms and molecular modelling studies
Full text linkOver the latest years phytochemical consumption has been associated to a decreased risk of both theonset and the development of a number of pathological conditions. In this context indicaxanthin, abetalain pigment fromOpuntiaficus-indicafruit, has been the object of sound research. Explored, atfirst,for its mere antioxidant potential, Indicaxanthin is now regarded as a redox-active compound able toexert significant poly-pharmacological effects against several targets in a number of experimental con-ditions bothin vivoandin vitro. This paper aims to provide an overview on the therapeutical effects ofindicaxanthin, ranging from the anti-inflammatory to the neuro-modulatory and anti-tumoral ones andfavored by its high bioavailability. Moreover, biochemical and molecular modelling investigations areaimed to identify the pharmacological targets the compound is able to interact with and to address thechallenging development in the future researc
Immunoproteasome and Non-Covalent Inhibition: Exploration by Advanced Molecular Dynamics and Docking Methods
Full text linkThe selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune, inflammatory diseases, and hematologic malignancies. Recently, a new series of amide derivatives as non-covalent inhibitors of the β1i subunit with Ki values in the low/submicromolar ranges have been identified. Here, we investigated the binding mechanism of the most potent and selective inhibitor, N-benzyl-2-(2-oxopyridin-1(2H)-yl)propanamide (1), to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400 ns of MD-binding analyses, followed by 200 ns of plain MD. The trajectories clustering allowed identifying three representative poses evidencing new key interactions with Phe31 and Lys33 together in a flipped orientation of a representative pose. Further, Binding Pose MetaDynamics (BPMD) studies were performed to evaluate the binding stability, comparing 1 with four other inhibitors of the β1i subunit: N-benzyl-2-(2-oxopyridin-1(2H)-yl)acetamide (2), N-cyclohexyl-3-(2-oxopyridin-1(2H)-yl)propenamide (3), N-butyl-3-(2-oxopyridin-1(2H)-yl)propanamide (4), and (S)-2-(2-oxopyridin-1(2H)-yl)-N,4-diphenylbutanamide (5). The obtained results in terms of free binding energy were consistent with the experimental values of inhibition, confirming 1 as a lead compound of this series. The adopted methods provided a full dynamic description of the binding events, and the information obtained could be exploited for the rational design of new and more active inhibitors
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
Virtual Screening Strategy and In Vitro Tests to Identify New Inhibitors of the Immunoproteasome
Full text linkImmunoproteasome inhibition is a promising strategy for the treatment of hematological malignancies, autoimmune diseases, and inflammatory diseases. The design of non-covalent inhibitors of the immunoproteasome beta 1i/beta 5i catalytic subunits could be a novel approach to avoid the drawbacks of the known covalent inhibitors, such as toxicity due to off-target binding. In this work, we report the biological evaluation of thirty-four compounds selected from a commercially available collection. These hit compounds are the outcomes of a virtual screening strategy including a dynamic pharmacophore modeling approach onto the beta 1i subunit and a pharmacophore/docking approach onto the beta 5i subunit. The computational studies were first followed by in vitro enzymatic assays at 100 mu M. Only compounds capable of inhibiting the enzymatic activity by more than 50% were characterized in detail using Tian continuous assays, determining the dissociation constant (K-i) of the non-covalent complex where K-i is also the measure of the binding affinity. Seven out of thirty-four hits showed to inhibit beta 1i and/or beta 5i subunit. Compound 3 is the most active on the beta 1i subunit with K-i = 11.84 +/- 1.63 mu M, and compound 17 showed K-i = 12.50 +/- 0.77 mu M on the beta 5i subunit. Compound 2 showed inhibitory activity on both subunits (K-i = 12.53 +/- 0.18 and K-i = 31.95 +/- 0.81 on the beta 1i subunit and beta 5i subunit, respectively). The induced fit docking analysis revealed interactions with Thr1 and Phe31 of beta 1i subunit and that represent new key residues as reported in our previous work. Onto beta 5i subunit, it interacts with the key residues Thr1, Thr21, and Tyr169. This last hit compound identified represents an interesting starting point for further optimization of beta 1i/beta 5i dual inhibitors of the immunoproteasome
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
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