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      The next-generation Open Targets Platform: reimagined, redesigned, rebuilt

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          Abstract

          The Open Targets Platform ( https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene–disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

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          Most cited references38

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          The mutational constraint spectrum quantified from variation in 141,456 humans

          Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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            The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets

            Abstract Cellular life depends on a complex web of functional associations between biomolecules. Among these associations, protein–protein interactions are particularly important due to their versatility, specificity and adaptability. The STRING database aims to integrate all known and predicted associations between proteins, including both physical interactions as well as functional associations. To achieve this, STRING collects and scores evidence from a number of sources: (i) automated text mining of the scientific literature, (ii) databases of interaction experiments and annotated complexes/pathways, (iii) computational interaction predictions from co-expression and from conserved genomic context and (iv) systematic transfers of interaction evidence from one organism to another. STRING aims for wide coverage; the upcoming version 11.5 of the resource will contain more than 14 000 organisms. In this update paper, we describe changes to the text-mining system, a new scoring-mode for physical interactions, as well as extensive user interface features for customizing, extending and sharing protein networks. In addition, we describe how to query STRING with genome-wide, experimental data, including the automated detection of enriched functionalities and potential biases in the user's query data. The STRING resource is available online, at https://string-db.org/.
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              UniProt: the universal protein knowledgebase in 2021

              (2020)
              Abstract The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this article, we describe significant updates that we have made over the last two years to the resource. The number of sequences in UniProtKB has risen to approximately 190 million, despite continued work to reduce sequence redundancy at the proteome level. We have adopted new methods of assessing proteome completeness and quality. We continue to extract detailed annotations from the literature to add to reviewed entries and supplement these in unreviewed entries with annotations provided by automated systems such as the newly implemented Association-Rule-Based Annotator (ARBA). We have developed a credit-based publication submission interface to allow the community to contribute publications and annotations to UniProt entries. We describe how UniProtKB responded to the COVID-19 pandemic through expert curation of relevant entries that were rapidly made available to the research community through a dedicated portal. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.
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                Author and article information

                Contributors
                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                06 January 2023
                18 November 2022
                18 November 2022
                : 51
                : D1
                : D1353-D1359
                Affiliations
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                GlaxoSmithKline plc, GSK Medicines Research Centre , Gunnels Wood Road, Stevenage, SG1 2NY, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                GlaxoSmithKline plc, GSK Medicines Research Centre , Gunnels Wood Road, Stevenage, SG1 2NY, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Wellcome Sanger Institute , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                Open Targets, Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
                Author notes
                To whom correspondence should be addressed. Tel: +44 1223 494330; Email: emcdonagh@ 123456ebi.ac.uk
                Correspondence may also be addressed to David Ochoa. Tel: +44 1223 494330; Email: ochoa@ 123456ebi.ac.uk
                Author information
                https://orcid.org/0000-0003-1857-278X
                https://orcid.org/0000-0002-7368-180X
                https://orcid.org/0000-0002-4623-8642
                https://orcid.org/0000-0003-2525-5598
                https://orcid.org/0000-0001-5806-6174
                Article
                gkac1046
                10.1093/nar/gkac1046
                9825572
                36399499
                76ac13f6-2ef9-4482-9615-5ec3a15dbadc
                © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 October 2022
                : 14 October 2022
                : 15 September 2022
                Page count
                Pages: 7
                Funding
                Funded by: Wellcome Trust, DOI 10.13039/100010269;
                Award ID: 206194
                Funded by: Open Targets;
                Categories
                AcademicSubjects/SCI00010
                Database Issue

                Genetics
                Genetics

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