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Identification of novel immune-relevant drug target genes for Alzheimer's Disease by combining ontology inference with network analysis.

ABSTRACT: AIMS:Alzheimer's disease (AD) is one of the leading causes of death in elderly people. Its pathogenesis is greatly associated with the abnormality of immune system. However, only a few immune-relevant AD drug target genes have been discovered up to now, and it is speculated that there are still many potential drug target genes of AD (at least immune-relevant genes) to be discovered. Thus, this study was designed to identify novel AD drug target genes and explore their biological properties. METHODS:A combinatorial approach was adopted for the first time to discover AD drug targets by collectively considering ontology inference and network analysis. Moreover, a novel strategy limiting the distance of reasoning and in turn reducing noise interference was further proposed to improve inference performance. Potential AD drug target genes were discovered by integrating information of multiple popular databases (TTD, DrugBank, PharmGKB, AlzGene, and BioGRID). Then, the enrichment analyses of the identified drug targets genes based on nine well-known pathway-related databases were conducted to explore the function of the identified potential drug target genes. RESULTS:Eighteen potential drug target genes were finally identified, and 13 of them had been reported to be closely associated with AD. Enrichment analyses of these identified drug target genes, based on nine pathway-related databases, revealed that the enriched terms were primarily focus on immune-relevant biological processes. Four of those identified drug target genes are involved in the classical complement pathway and process of antigen presenting. CONCLUSION:The well-reproducible results showed the good performance of the combinatorial approach, and the remaining five new targets could be a good starting point for our understanding of the pathogenesis and drug discovery of AD. Moreover, this study supported validity of the combinatorial approach integrating ontology inference with network analysis in the discovery of novel drug target for neurological diseases.

SUBMITTER: Han ZJ

PROVIDER: S-EPMC6489817 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Identification of novel immune-relevant drug target genes for Alzheimer's Disease by combining ontology inference with network analysis.

Han Zhi-Jie ZJ Xue Wei-Wei WW Tao Lin L Zhu Feng F

CNS neuroscience & therapeutics 20180814 12

<h4>Aims</h4>Alzheimer's disease (AD) is one of the leading causes of death in elderly people. Its pathogenesis is greatly associated with the abnormality of immune system. However, only a few immune-relevant AD drug target genes have been discovered up to now, and it is speculated that there are still many potential drug target genes of AD (at least immune-relevant genes) to be discovered. Thus, this study was designed to identify novel AD drug target genes and explore their biological properti ...[more]

PMID: 30106219

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Project description:BACKGROUND:One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. RESULTS:As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. CONCLUSIONS:DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource.

Project description:The process of discovering new drugs is a lengthy, time-consuming and expensive process. Modern day drug discovery relies heavily on the rapid identification of novel 'targets', usually proteins that can be modulated by small molecule drugs to cure or minimise the effects of a disease. Of the 20,000 proteins currently reported as comprising the human proteome, just under a quarter of these can potentially be modulated by known small molecules Storing information in curated, actively maintained drug discovery databases can help researchers access current drug discovery information quickly. However with the increase in the amount of data generated from both experimental and in silico efforts, databases can become very large very quickly and information retrieval from them can become a challenge. The development of database tools that facilitate rapid information retrieval is important to keep up with the growth of databases.We have developed a Gene Ontology-based navigation tool (Gene Ontology Tree) to help users retrieve biological information to single protein targets in the ChEMBL drug discovery database. 99 % of single protein targets in ChEMBL have at least one GO annotation associated with them. There are 12,500 GO terms associated to 6200 protein targets in the ChEMBL database resulting in a total of 140,000 annotations. The slim we have created, the 'ChEMBL protein target slim' allows broad categorisation of the biology of 90 % of the protein targets using just 300 high level, informative GO terms. We used the GO slim method of assigning fewer higher level GO groupings to numerous very specific lower level terms derived from the GOA to describe a set of GO terms relevant to proteins in ChEMBL. We then used the slim created to provide a web based tool that allows a quick and easy navigation of protein target space. Terms from the GO are used to capture information on protein molecular function, biological process and subcellular localisations. The ChEMBL database also provides compound information for small molecules that have been tested for their effects on these protein targets. The 'ChEMBL protein target slim' provides a means of firstly describing the biology of protein drug targets and secondly allows users to easily establish a connection between biological and chemical information regarding drugs and drug targets in ChEMBL. The 'ChEMBL protein target slim' is available as a browsable 'Gene Ontology Tree' on the ChEMBL site under the browse targets tab ( https://www.ebi.ac.uk/chembl/target/browser ). A ChEMBL protein target slim OBO file containing the GO slim terms pertinent to ChEMBL is available from the GOC website ( http://geneontology.org/page/go-slim-and-subset-guide ).We have created a protein target navigation tool based on the 'ChEMBL protein target slim'. The 'ChEMBL protein target slim' provides a way of browsing protein targets in ChEMBL using high level GO terms that describe the molecular functions, processes and subcellular localisations of protein drug targets in drug discovery. The tool also allows user to establish a link between ontological groupings representing protein target biology to relevant compound information in ChEMBL. We have demonstrated by the use of a simple example how the 'ChEMBL protein target slim' can be used to link biological processes with drug information based on the information in the ChEMBL database. The tool has potential to aid in areas of drug discovery such as drug repurposing studies or drug-disease-protein pathways.

Dataset Information

Identification of novel immune-relevant drug target genes for Alzheimer's Disease by combining ontology inference with network analysis.

Publications

Identification of novel immune-relevant drug target genes for Alzheimer's Disease by combining ontology inference with network analysis.

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