Publications Search
Explore how scientists all over the world use DrugBank in their research.
Showing 2961 to 2964 of 5186 entries
Published on July 2, 2019
Drug ReposER: a web server for predicting similar amino acid arrangements to known drug binding interfaces for potential drug repositioning.
Abstract: A common drug repositioning strategy is the re-application of an existing drug to address alternative targets. A crucial aspect to enable such repurposing is that the drug's binding site on the original target is similar to that on the alternative target. Based on the assumption that proteins with similar binding sites may bind to similar drugs, the 3D substructure similarity data can be used to identify similar sites in other proteins that are not known targets. The Drug ReposER (DRug REPOSitioning Exploration Resource) web server is designed to identify potential targets for drug repurposing based on sub-structural similarity to the binding interfaces of known drug binding sites. The application has pre-computed amino acid arrangements from protein structures in the Protein Data Bank that are similar to the 3D arrangements of known drug binding sites thus allowing users to explore them as alternative targets. Users can annotate new structures for sites that are similarly arranged to the residues found in known drug binding interfaces. The search results are presented as mappings of matched sidechain superpositions. The results of the searches can be visualized using an integrated NGL viewer. The Drug ReposER server has no access restrictions and is available at http://mfrlab.org/drugreposer/.
Published on July 2, 2019
NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis.
Abstract: The growing application of gene expression profiling demands powerful yet user-friendly bioinformatics tools to support systems-level data understanding. NetworkAnalyst was first released in 2014 to address the key need for interpreting gene expression data within the context of protein-protein interaction (PPI) networks. It was soon updated for gene expression meta-analysis with improved workflow and performance. Over the years, NetworkAnalyst has been continuously updated based on community feedback and technology progresses. Users can now perform gene expression profiling for 17 different species. In addition to generic PPI networks, users can now create cell-type or tissue specific PPI networks, gene regulatory networks, gene co-expression networks as well as networks for toxicogenomics and pharmacogenomics studies. The resulting networks can be customized and explored in 2D, 3D as well as Virtual Reality (VR) space. For meta-analysis, users can now visually compare multiple gene lists through interactive heatmaps, enrichment networks, Venn diagrams or chord diagrams. In addition, users have the option to create their own data analysis projects, which can be saved and resumed at a later time. These new features are released together as NetworkAnalyst 3.0, freely available at https://www.networkanalyst.ca.
Published on July 1, 2019
Binding site characterization - similarity, promiscuity, and druggability.
Abstract: The elucidation of non-obvious binding site similarities has provided useful indications for the establishment of polypharmacology, the identification of potential off-targets, or the repurposing of known drugs. The concept underlying all of these approaches is promiscuous binding which can be analyzed from a ligand-based or a binding site-based perspective. Herein, we applied methods for the automated analysis and comparison of protein binding sites to study promiscuous binding on a novel dataset of sites in complex with ligands sharing common shape and physicochemical properties. We show the suitability of this dataset for the benchmarking of novel binding site comparison methods. Our investigations also reveal promising directions for further in-depth analyses of promiscuity and druggability in a pocket-centered manner. Drawbacks concerning binding site similarity assessment and druggability prediction are outlined, enabling researchers to avoid the typical pitfalls of binding site analyses.
Published in June 2019
Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Abstract: Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Published on June 30, 2019
Large-Scale Target Identification of Herbal Medicine Using a Reverse Docking Approach.
Abstract: Herbal medicine has been used to countermine various diseases for centuries. However, most of the therapeutic targets underlying herbal therapy remain unclear, which largely slow down the novel drug discovery process from natural products. In this study, we developed a novel computational pipeline for assisting de novo identification of protein targets for herbal ingredients. The pipeline involves pharmacophore comparison and reverse ligand-protein docking simulation in a high throughput manner. We evaluated the pipeline using three traditional Chinese medicine ingredients such as acteoside, quercetin, and epigallocatechin gallate as examples. A majority of current known targets of these ingredients were successfully identified by the pipeline. Structural comparative analyses confirmed that the predicted ligand-target interactions used the same binding pockets and binding modes as those of known ligand-target interactions. Furthermore, we illustrated the mechanism of actions of the ingredients by constructing the pharmacological networks on the basis of the predicted target profiles. In summary, we proposed an efficient and economic option for large-scale target exploration in the herb study. This pipeline will be particularly valuable in aiding precise drug discovery and drug repurposing from natural products.
Published in June 2019
Rational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology.
Abstract: Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line's and a patient's response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases.
Published in June 2019
Mapping human microbiome drug metabolism by gut bacteria and their genes.
Abstract: Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.
Published in June 2019
DeepConv-DTI: Prediction of drug-target interactions via deep learning with convolution on protein sequences.
Abstract: Identification of drug-target interactions (DTIs) plays a key role in drug discovery. The high cost and labor-intensive nature of in vitro and in vivo experiments have highlighted the importance of in silico-based DTI prediction approaches. In several computational models, conventional protein descriptors have been shown to not be sufficiently informative to predict accurate DTIs. Thus, in this study, we propose a deep learning based DTI prediction model capturing local residue patterns of proteins participating in DTIs. When we employ a convolutional neural network (CNN) on raw protein sequences, we perform convolution on various lengths of amino acids subsequences to capture local residue patterns of generalized protein classes. We train our model with large-scale DTI information and demonstrate the performance of the proposed model using an independent dataset that is not seen during the training phase. As a result, our model performs better than previous protein descriptor-based models. Also, our model performs better than the recently developed deep learning models for massive prediction of DTIs. By examining pooled convolution results, we confirmed that our model can detect binding sites of proteins for DTIs. In conclusion, our prediction model for detecting local residue patterns of target proteins successfully enriches the protein features of a raw protein sequence, yielding better prediction results than previous approaches. Our code is available at https://github.com/GIST-CSBL/DeepConv-DTI.
Published in June 2019
An Integrated Approach to Recognize Potential Protective Effects of Culinary Herbs Against Chronic Diseases.
Abstract: Secondary metabolites in plants have been of interest to humans for their wide variety of functions, including its use as dye, drugs, or perfumes. They are increasingly recognized as potential sources of new natural drugs and antibiotics. More recently, gut-associated microbes have been found to fulfill important functions in human health. However, our knowledge about the impact of secondary metabolites from culinary herbs on gut microbiome is limited. The present study was conducted to access the availability of computational resources relating to secondary metabolites and bioactive compounds in culinary herbs. A graph-based database HerbMicrobeDataBase (HMDB) was developed using Neo4j framework. It integrates knowledge from key biological entities associated in maintaining gut health and provides efficient storage/retrieval and graphical presentation of botanical, biochemical, and pharmacological data for culinary herbs and the human microbiome. We demonstrate the utility of this resource in understanding the molecular mechanism of metabolite production as well as their therapeutic or toxicological effects on gut microbes.
Published in June 2019
A review of drug knowledge discovery using BioNLP and tensor or matrix decomposition.
Abstract: Prediction of the relations among drug and other molecular or social entities is the main knowledge discovery pattern for the purpose of drug-related knowledge discovery. Computational approaches have combined the information from different sources and levels for drug-related knowledge discovery, which provides a sophisticated comprehension of the relationship among drugs, targets, diseases, and targeted genes, at the molecular level, or relationships among drugs, usage, side effect, safety, and user preference, at a social level. In this research, previous work from the BioNLP community and matrix or matrix decomposition was reviewed, compared, and concluded, and eventually, the BioNLP open-shared task was introduced as a promising case study representing this area.
Showing 2961 to 2964 of 5186 entries