scholarly journals Integrated Analysis Identifies Interaction Patterns between Small Molecules and Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yan Li ◽  
Weiguo Li ◽  
Xin Chen ◽  
Hong Jiang ◽  
Jiatong Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Molecules ◽  
Drug Targets ◽  
Cancer Cell Line ◽  
Integrated Analysis ◽  
Interaction Patterns ◽  
Drug Candidates ◽  
Molecularly Targeted Therapy ◽  
Topological Characteristics ◽  
Potential Drug Targets

Previous studies have indicated that the downstream proteins in a key pathway can be potential drug targets and that the pathway can play an important role in the action of drugs. So pathways could be considered as targets of small molecules. A link map between small molecules and pathways was constructed using gene expression profile, pathways, and gene expression of cancer cell line intervened by small molecules and then we analysed the topological characteristics of the link map. Three link patterns were identified based on different drug discovery implications for breast, liver, and lung cancer. Furthermore, molecules that significantly targeted the same pathways tended to treat the same diseases. These results can provide a valuable reference for identifying drug candidates and targets in molecularly targeted therapy.

Drugs for Targeted Therapies of Alzheimer’s Disease

2019 ◽  
Vol 26 (2) ◽  
pp. 335-359 ◽  
Author(s):  
Chit Tam ◽  
Jack Ho Wong ◽  
Tzi Bun Ng ◽  
Stephen Kwok Wing Tsui ◽  
Tao Zuo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Drug Targets ◽  
The Elderly ◽  
Dependent Manner ◽  
Cell Replacement Therapy ◽  
Drug Candidates ◽  
Amyloid A ◽  
Potential Drug Targets

Alzheimer’s disease (AD) is one type of neurodegenerative diseases, which is prevalent in the elderly. Beta-amyloid (Aβ) plaques and phosphorylated tau-induced neurofibrillary tangles are two pathological hallmarks of this disease and the corresponding pathological pathways of these hallmarks are considered as the therapeutic targets. There are many drugs scheduled for pre-clinical and clinical trial that target to inhibit the initiators of pathological Aβ and tau aggregates as well as critical Aβ secretases and kinases in tau hyperphosphorylation. In addition, studies in disease gene variations, and detection of key prognostic effectors in early development are also important for AD control. The discovery of potential drug targets contributed to targeted therapy in a stage-dependent manner, However, there are still some issues that cause concern such as the low bioavailability and low efficacy of candidate drugs from clinical trial reports. Therefore, modification of drug candidates and development of delivery agents are essential and critical. With other medical advancements like cell replacement therapy, there is hope for the cure of Alzheimer’s disease in the foreseeable future.

scholarly journals Transcriptomic Signatures and Functional Network Analysis of Chronic Rhinosinusitis With Nasal Polyps

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Hao ◽  
Yan Zhao ◽  
Ping Wang ◽  
Kun Du ◽  
Ying Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Molecular Mechanisms ◽  
Sinus Surgery ◽  
Receptor Interaction ◽  
Integrated Analysis ◽  
Healthy Controls ◽  
Drug Candidates

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic sinonasal inflammatory disease with limited treatment options of corticosteroids, sinus surgery, or both. CRSwNP is frequently associated with allergic rhinitis and asthma, but the molecular mechanisms underlying CRSwNP inflammation are not completely understood. We obtained four gene expression profiles (GSE136825, GSE36830, GSE23552, and GSE72713) from four Gene Expression Omnibus (GEO), which collectively included 65 nasal polyp samples from CRSwNP patients and 54 nasal mucosal samples from healthy controls. Using an integrated analysis approach, we identified 76 co-differentially expressed genes (co-DEGs, including 45 upregulated and 31 downregulated) in CRSwNP patients compared with the healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified the terms including immune effector process, leukocyte migration, regulation of the inflammatory response, Staphylococcus aureus infection, and cytokine-cytokine receptor interaction. protein-protein interaction (PPI) network analysis and real-time quantitative PCR (RT-qPCR) showed that 7 genes might be crucial in CRSwNP pathogenesis. Repurposing drug candidates (Alfadolone, Hydralazine, SC-560, Iopamidol, Iloprost, etc) for CRSwNP treatment were identified from the Connectivity Map (CMap) database. Our results suggest multiple molecular mechanisms, diagnostic biomarkers, potential therapeutic targets, and new repurposing drug candidates for CRSwNP treatment.

Potential Drug Targets Identification against Clostridioides difficile (CD) and Characterization of Indispensable Proteins by a Subtractive Genomics Approach Followed by Virtual Screening

2021 ◽  
Vol 18 ◽  
Author(s):  
Reaz Uddin ◽  
Alina Arif
Keyword(s):  
Drug Targets ◽  
Drug Resistant ◽  
Potential Drug ◽  
Drug Candidates ◽  
Subtractive Genomics ◽  
Clostridioides Difficile ◽  
Subtractive Genomics Approach ◽  
Novel Drug ◽  
Potential Drug Targets ◽  
Novel Drug Targets

Background: Clostridioides difficile (CD) is a multi-drug resistant, enteric pathogenic bacterium. The CD associated infections are the leading cause of nosocomial diarrhea that can further lead to pseudomembranous colitis up to a toxic mega-colon or sepsis with greater mortality and morbidity risks. The CD infection possess higher rates of recurrence due to its greater resistance against antibiotics. Considering its higher rates of recurrence, it has become a major burden on the healthcare facilities. Therefore, there is a dire need to identify novel drug targets to combat with the antibiotic resistance of Clostridioides difficile. Objective: To identify and propose new and novel drug targets against the Clostridioides difficile. Methods: In the current study, a computational subtractive genomics approach was applied to obtain a set of potential drug targets that exists in the multi-drug resistant strain of Clostridioides difficile. Here, the uncharacterized proteins were studied as potential drug targets. The methodology involved several bioinformatics databases and tools. The druggable proteins sequences were retrieved based on non-homology with host proteome and essentiality for the survival of the pathogen. The uncharacterized proteins were functionally characterized using different computational tools and sub-cellular localization was also predicted. The metabolic pathways were analyzed using KEGG database. Eventually, the druggable proteome has been fetched using sequence similarity with the already available drug targets present in DrugBank database. These druggable proteins were further explored for the structural details to identify drug candidates. Results : A priority list of potential drug targets was provided with the help of the applied method on complete proteome set of the C. difficile. Moreover, the drug like compounds have been screened against the potential drug targets to prioritize potential drug candidates. To facilitate the need for drug targets and therapies, the study proposed five potential protein drug targets out of which three proposed drug targets were subjected to homology modeling to explore their structural and functional activities. Conclusion: In conclusion, we proposed three unique, unexplored drug targets against C. difficile. The structure-based methods were applied and resulted in a list of top scoring compounds as potential inhibitors to proposed drug targets.

scholarly journals Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

2020 ◽  
Author(s):  
Chengran Yang ◽  
Fabiana G. Farias ◽  
Laura Ibanez ◽  
Brooke Sadler ◽  
Maria Victoria Fernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Drug Targets ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Protein Levels ◽  
Genome Wide ◽  
Novel Biomarkers ◽  
Potential Drug Targets

AbstractExpression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits1–6. However, there is a need for implementing additional “omic” approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. In the context of personalized medicine, these results highlight the need for implementing additional functional genomic approaches beyond gene expression in order to understand the biology of complex traits, and to identify novel biomarkers and potential drug targets for those traits.

scholarly journals Identification of Candidate Drugs for Heart Failure using Tensor Decomposition-Based Unsupervised Feature Extraction Applied to Integrated Analysis of Gene Expression between Heart Failure and DrugMatrix Datasets

2017 ◽  
Author(s):  
Y-h. Taguchi
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Feature Extraction ◽  
Drug Target ◽  
Drug Targets ◽  
Target Genes ◽  
Expression Profiles ◽  
Tensor Decomposition ◽  
Integrated Analysis ◽  
Unsupervised Feature Extraction

AbstractIdentifying drug target genes in gene expression profiles is not straightforward. Because a drug targets not mRNAs but proteins, mRNA expression of drug target genes is not always altered. In addition, the interaction between a drug and protein can be context dependent; this means that simple drug incubation experiments on cell lines do not always reflect the real situation during active disease. In this paper, I apply tensor decomposition-based unsupervised feature extraction to the integrated analysis of gene expression between heart failure and the DrugMatrix dataset where comprehensive data on gene expression during various drug treatments of rats were reported. I found that this strategy, in a fully unsupervised manner, enables us to identify a combined set of genes and compounds, for which various associations with heart failure were reported.

scholarly journals Rhinovirus Inhibitors: Including a New Target, the Viral RNA

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1784
Author(s):  
Antonio Real-Hohn ◽  
Dieter Blaas
Keyword(s):  
Drug Targets ◽  
Enterovirus 71 ◽  
Cell Receptor ◽  
Viral Rna ◽  
Potential Drug ◽  
Drug Candidates ◽  
Fda Approval ◽  
G Quadruplex ◽  
Life Threatening ◽  
Potential Drug Targets

Rhinoviruses (RVs) are the main cause of recurrent infections with rather mild symptoms characteristic of the common cold. Nevertheless, RVs give rise to enormous numbers of absences from work and school and may become life-threatening in particular settings. Vaccination is jeopardised by the large number of serotypes eliciting only poorly cross-neutralising antibodies. Conversely, antivirals developed over the years failed FDA approval because of a low efficacy and/or side effects. RV species A, B, and C are now included in the fifteen species of the genus Enteroviruses based upon the high similarity of their genome sequences. As a result of their comparably low pathogenicity, RVs have become a handy model for other, more dangerous members of this genus, e.g., poliovirus and enterovirus 71. We provide a short overview of viral proteins that are considered potential drug targets and their corresponding drug candidates. We briefly mention more recently identified cellular enzymes whose inhibition impacts on RVs and comment novel approaches to interfere with infection via aggregation, virus trapping, or preventing viral access to the cell receptor. Finally, we devote a large part of this article to adding the viral RNA genome to the list of potential drug targets by dwelling on its structure, folding, and the still debated way of its exit from the capsid. Finally, we discuss the recent finding that G-quadruplex stabilising compounds impact on RNA egress possibly via obfuscating the unravelling of stable secondary structural elements.

scholarly journals NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 904 ◽  
Author(s):  
Ángel Cores ◽  
Marta Piquero ◽  
Mercedes Villacampa ◽  
Rafael León ◽  
J. Carlos Menéndez
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Phase Ii ◽  
Drug Targets ◽  
Antioxidant Response ◽  
Potential Drug ◽  
Critical Overview ◽  
Potential Drug Targets ◽  
Potential Use

NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.

scholarly journals A Perspective on Extreme Open Science: Companies Sharing Compounds without Restriction

2019 ◽  
Vol 24 (5) ◽  
pp. 505-514 ◽  
Author(s):  
David H. Drewry ◽  
Carrow I. Wells ◽  
William J. Zuercher ◽  
Timothy M. Willson
Keyword(s):  
Dark Matter ◽  
Drug Discovery ◽  
Small Molecules ◽  
Drug Targets ◽  
Scientific Community ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Potential Drug ◽  
Potential Drug Targets ◽  
Shed Light

Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. This perspective describes how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. The integration of open science and kinase chemogenomics has supported the study of many new potential drug targets by the scientific community.

scholarly journals The Bioinformatic Analysis of the Dysregulated Genes and MicroRNAs in Entorhinal Cortex, Hippocampus, and Blood for Alzheimer’s Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Xiaocong Pang ◽  
Ying Zhao ◽  
Jinhua Wang ◽  
Qimeng Zhou ◽  
Lvjie Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Entorhinal Cortex ◽  
Drug Targets ◽  
Target Genes ◽  
Bioinformatic Analysis ◽  
Hub Genes ◽  
Pathway Enrichment

Aim. The incidence of Alzheimer’s disease (AD) has been increasing in recent years, but there exists no cure and the pathological mechanisms are not fully understood. This study aimed to find out the pathogenesis of learning and memory impairment, new biomarkers, potential therapeutic targets, and drugs for AD. Methods. We downloaded the microarray data of entorhinal cortex (EC) and hippocampus (HIP) of AD and controls from Gene Expression Omnibus (GEO) database, and then the differentially expressed genes (DEGs) in EC and HIP regions were analyzed for functional and pathway enrichment. Furthermore, we utilized the DEGs to construct coexpression networks to identify hub genes and discover the small molecules which were capable of reversing the gene expression profile of AD. Finally, we also analyzed microarray and RNA-seq dataset of blood samples to find the biomarkers related to gene expression in brain. Results. We found some functional hub genes, such as ErbB2, ErbB4, OCT3, MIF, CDK13, and GPI. According to GO and KEGG pathway enrichment, several pathways were significantly dysregulated in EC and HIP. CTSD and VCAM1 were dysregulated significantly in blood, EC, and HIP, which were potential biomarkers for AD. Target genes of four microRNAs had similar GO_terms distribution with DEGs in EC and HIP. In addtion, small molecules were screened out for AD treatment. Conclusion. These biological pathways and DEGs or hub genes will be useful to elucidate AD pathogenesis and identify novel biomarkers or drug targets for developing improved diagnostics and therapeutics against AD.

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