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Showing 3241 to 3244 of 5186 entries
Published in 2018
Discovery of nonnucleoside inhibitors of polymerase from infectious pancreatic necrosis virus (IPNV).
Abstract: Introduction: Infectious pancreatic necrosis virus (IPNV) causes serious losses in several fish species of commercial interest. IPNV is a non-enveloped double-stranded RNA virus with a genome consisting of two segments A and B. Segment B codes for the VP1 protein, a non-canonical RNA-dependent RNA polymerase that can be found both in its free form and linked to the end of genomic RNA, an essential enzyme for IPNV replication. Materials and methods: We take advantage of the knowledge over the allosteric binding site described on the surface of the thumb domain of Hepatitis C virus (HCV) polymerase to design new non-nucleoside inhibitors against the IPNV VP1 polymerase. Results: Molecular docking techniques have been used to screen a chemical library of 23,760 compounds over a defined cavity in the surface of the thumb domain. Additional ADMET (absorption, distribution, metabolism, excretion, and toxicity) filter criteria has been applied. Conclusion: We select two sets of 9 and 50 inhibitor candidates against the polymerases of HCV and IPNV, respectively. Two non-toxic compounds have been tested in vitro with antiviral capacity against IPNV Sp and LWVRT60 strains in the low microM range with different activity depending on the IPNV strain used.
Published in 2018
OpenPVSignal: Advancing Information Search, Sharing and Reuse on Pharmacovigilance Signals via FAIR Principles and Semantic Web Technologies.
Abstract: Signal detection and management is a key activity in pharmacovigilance (PV). When a new PV signal is identified, the respective information is publicly communicated in the form of periodic newsletters or reports by organizations that monitor and investigate PV-related information (such as the World Health Organization and national PV centers). However, this type of communication does not allow for systematic access, discovery and explicit data interlinking and, therefore, does not facilitate automated data sharing and reuse. In this paper, we present OpenPVSignal, a novel ontology aiming to support the semantic enrichment and rigorous communication of PV signal information in a systematic way, focusing on two key aspects: (a) publishing signal information according to the FAIR (Findable, Accessible, Interoperable, and Re-usable) data principles, and (b) exploiting automatic reasoning capabilities upon the interlinked PV signal report data. OpenPVSignal is developed as a reusable, extendable and machine-understandable model based on Semantic Web standards/recommendations. In particular, it can be used to model PV signal report data focusing on: (a) heterogeneous data interlinking, (b) semantic and syntactic interoperability, (c) provenance tracking and (d) knowledge expressiveness. OpenPVSignal is built upon widely-accepted semantic models, namely, the provenance ontology (PROV-O), the Micropublications semantic model, the Web Annotation Data Model (WADM), the Ontology of Adverse Events (OAE) and the Time ontology. To this end, we describe the design of OpenPVSignal and demonstrate its applicability as well as the reasoning capabilities enabled by its use. We also provide an evaluation of the model against the FAIR data principles. The applicability of OpenPVSignal is demonstrated by using PV signal information published in: (a) the World Health Organization's Pharmaceuticals Newsletter, (b) the Netherlands Pharmacovigilance Centre Lareb Web site and (c) the U.S. Food and Drug Administration (FDA) Drug Safety Communications, also available on the FDA Web site.
Published on December 28, 2018
A combined computational and experimental approach reveals the structure of a C/EBPbeta-Spi1 interaction required for IL1B gene transcription.
Abstract: We previously reported that transcription of the human IL1B gene, encoding the proinflammatory cytokine interleukin 1beta, depends on long-distance chromatin looping that is stabilized by a mutual interaction between the DNA-binding domains (DBDs) of two transcription factors: Spi1 proto-oncogene at the promoter and CCAAT enhancer-binding protein (C/EBPbeta) at a far-upstream enhancer. We have also reported that the C-terminal tail sequence beyond the C/EBPbeta leucine zipper is critical for its association with Spi1 via an exposed residue (Arg-232) located within a pocket at one end of the Spi1 DNA-recognition helix. Here, combining in vitro interaction studies with computational docking and molecular dynamics of existing X-ray structures for the Spi1 and C/EBPbeta DBDs, along with the C/EBPbeta C-terminal tail sequence, we found that the tail sequence is intimately associated with Arg-232 of Spi1. The Arg-232 pocket was computationally screened for small-molecule binding aimed at IL1B transcription inhibition, yielding l-arginine, a known anti-inflammatory amino acid, revealing a potential for disrupting the C/EBPbeta-Spi1 interaction. As evaluated by ChIP, cultured lipopolysaccharide (LPS)-activated THP-1 cells incubated with l-arginine had significantly decreased IL1B transcription and reduced C/EBPbeta's association with Spi1 on the IL1B promoter. No significant change was observed in direct binding of either Spi1 or C/EBPbeta to cognate DNA and in transcription of the C/EBPbeta-dependent IL6 gene in the same cells. These results support the notion that disordered sequences extending from a leucine zipper can mediate protein-protein interactions and can serve as druggable targets for regulating gene promoter activity.
Published on December 26, 2018
Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.
Abstract: Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.
Published on December 25, 2018
GenCoNet - A Graph Database for the Analysis of Comorbidities by Gene Networks.
Abstract: The prevalence of comorbid diseases poses a major health issue for millions of people worldwide and an enormous socio-economic burden for society. The molecular mechanisms for the development of comorbidities need to be investigated. For this purpose, a workflow system was developed to aggregate data on biomedical entities from heterogeneous data sources. The process of integrating and merging all data sources of the workflow system was implemented as a semi-automatic pipeline that provides the import, fusion, and analysis of the highly connected biomedical data in a Neo4j database GenCoNet. As a starting point, data on the common comorbid diseases essential hypertension and bronchial asthma was integrated. GenCoNet (https://genconet.kalis-amts.de) is a curated database that provides a better understanding of hereditary bases of comorbidities.
Published on December 21, 2018
A Model Integration Pipeline for the Improvement of Human Genome-Scale Metabolic Reconstructions.
Abstract: Metabolism has been a major field of study in the last years, mainly due to its importance in understanding cell physiology and certain disease phenotypes due to its deregulation. Genome-scale metabolic models (GSMMs) have been established as important tools to help achieve a better understanding of human metabolism. Towards this aim, advances in systems biology and bioinformatics have allowed the reconstruction of several human GSMMs, although some limitations and challenges remain, such as the lack of external identifiers for both metabolites and reactions. A pipeline was developed to integrate multiple GSMMs, starting by retrieving information from the main human GSMMs and evaluating the presence of external database identifiers and annotations for both metabolites and reactions. Information from metabolites was included into a graph database with omics data repositories, allowing clustering of metabolites through their similarity regarding database cross-referencing. Metabolite annotation of several older GSMMs was enriched, allowing the identification and integration of common entities. Using this information, as well as other metrics, we successfully integrated reactions from these models. These methods can be leveraged towards the creation of a unified consensus model of human metabolism.
Published on December 21, 2018
Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods.
Abstract: The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed. Molecular docking of nitrogen mustards (NMs) with a wide range of affinity allowed for deriving a common binding mode that could explain the structure-activity relationship pattern in NMs. Subsequently, validated binding hypotheses were subjected to molecular dynamics simulation, which allowed for extracting a set of dynamic pharmacophores. Finally, a library of ~1.1 million molecules was virtually screened against these pharmacophores, followed by docking. Biological testing of the 30 top-ranked hits revealed 13 actives, with the best compound showing an IC50 value in the sub-muM range.
Published on December 21, 2018
A guide to maximizing the therapeutic potential of protein-polymer conjugates by rational design.
Abstract: Proteins are an important class of therapeutics that have advantages including high target specificity, but challenges to their use include rapid clearance and low physical stability. Conjugation of synthetic polymers is an effective approach to address the drawbacks and enhance other properties such as solubility. In this review, we present various considerations in synthesizing protein-polymer conjugates for therapeutic applications with a focus on the choice of polymer, protein, and conjugation method, as well as characterization and evaluation of the resulting conjugate in order to maximize the therapeutic potential of the protein drug.
Published on December 20, 2018
Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations.
Abstract: BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. RESULTS: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. CONCLUSIONS: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.
Published on December 19, 2018
In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives.
Abstract: BACKGROUND: Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones. RESULTS: The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 muM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 muM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 muM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol. CONCLUSIONS: These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.
Showing 3241 to 3244 of 5186 entries