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EMBL-EBI Chemogenomics and drug discovery Previous and current research The human genome project has delivered huge potential for the discovery of novel therapeutics. In sharp contrast to this potential and promise is the small actual translation of functional genomics discoveries into clinically useful agents. The goal of our group is to understand the signalling, regulatory and physicochemical characteristics of historically successful drug targets, and to provide predictive methods to prioritise future potential drug targets. Our lab relies of a series of public domain databases to perform its research, many of which have been built and developed within our own group. These databases cover medicinal chemistry, clinical development and launched drugs, and are known by the name ChEMBL. Additionally, all our work is computational although we have collaborations with key experimental groups. Finally, we apply a broad range of knowledge discovery from data (KDD), data visualisation, and predictive methods in our work. Key to the assessment of future drug targets is an integrative approach which can consider biochemical binding data, alongside functional and systemic effects and also include protein structure and binding site data. As such we apply a uniquely broad set of approaches from cheminformatics, bioinformatics, homology modelling, docking and machine learning. We are a newly established group at EMBL-EBI, following the award of a grant from the Wellcome Trust to transfer our previous databases and research from the private to public domain. John Overington PhD 1991, Birkbeck College, University of London. Postdoctoral work at Imperial Cancer Research Fund. Manager, Molecular Informatics Structure and Design, Pfizer, Sandwich. Senior Director, Molecular Informatics, Inpharmatica. Team leader at EMBL-EBI since 2008. Future projects and goals We are interested in the informatics-based prioritisation of drug targets for application in the area of neglected diseases, in particular those diseases caused by pathogenic organisms. We are also interested in data-mining approaches to allow semi-automated design and optimisation of hit and lead chemical series using generalisation of systematic rules discovered in our databases. Finally we have a strong interest in the application of these techniques for newer classes of therapeutics such as monoclonal antibodies (mAbs) and non-human secreted proteins (for example, helminth proteins that naturally suppress immune response in the host organism). Selected references Agüero, F. et al. (2008). Genomic-scale prioritisation of drug targets: TDRtargets.org. Nat. Rev. Drug. Discov., 7, 900-907 Hopkins, A.L., Mason, J.S. & Overington, J.P. (2006) Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol., 16, 127-136 Overington, J.P., Al-Lazikani, B. & Hopkins, A.L. (2006) How many drug targets are there? Nat. Rev. Drug Discov., 5, 993-996 Danilewicz, J.C. et al. (2002). Design and synthesis of thrombin inhibitors based on the (R)-Phe-Pro-Arg sequence. J. Med. Chem., 5, 232-253 Mizuguchi, K. et al. (1998). HOMSTRAD: a database of protein structure alignments and homologous families. Protein Science, 7, 269-271 81
EMBL Research at a Glance 2009 Peter Rice BSc 1976, University of Liverpool. Previously at EMBL Heidelberg (1987–199), the Sanger Centre (199–2000) and LION Bioscience (2000– 2002). Team leader at EMBL-EBI since 2003. Grid and e-Science research and development Previous and current research The team’s focus is on the integration of bioinformatics tools and data resources. We have the remit to investigate and advise on the e-Science and Grid technology requirements of EMBL-EBI, through application development, training exercises and participation in international projects and standards development. Our group is responsible for the EMBOSS open source sequence analysis package, the Taverna bioinformatics workflow system (originally developed as part of the myGrid UK e-Science project) and for various projects (including EMBRACE and ComparaGrid) that integrate access to bioinformatics tools and data content. To date, Grid development has focussed on the basic issues of storage, computation and resource management needed to make a global scientific community’s information and tools accessible in a high-performance environment. However, from the e-Science point of view, the purpose of the Grid is to deliver a collaborative and supportive environment that enables geographically distributed scientists to achieve research goals more effectively, while allowing their results to be used in developments elsewhere. Our group has been the biological specialist participant in the UK-funded myGrid project and this collaboration is continuing with the Open Middleware Infrastructure Institute (OMII-UK). This project was aimed at developing and maintaining open source high-level service-based middleware to support the construction, management and sharing of data-intensive in silico experiments in biology. EMBL-EBI’s role is through the Taverna workbench and as an application and data service developer and provider which continues through the EMBRACE and EMBOSS projects. A key factor in the success of EMBOSS, and in particular its selection as the application platform for the EMBRACE and myGrid projects, has been its development and implementation of the AJAX Command Definition standard or ACD files. These define the interface of each EMBOSS application and are directly used by the application on startup for all processing of the command line and interaction with the user. The EMBRACE project, an EU-funded Network of Excellence, is now in its second year, with the aim of defining and implementing a consistent standard interface to integrate data content and analysis tools across all EMBL-EBI core databases and those provided by our partners. The early focus of this five-year project has been on the sequence and structure data resources at EBI and the EMBOSS applications. Our group is also active in defining the core technologies to be used by EMBRACE, including BioMart data federation methods, web services provided by the EBI External Services team, and the Taverna workbench as an end-user client. Future projects and goals The services provided by the group remain largely SOAP-based web services. These have proved to be highly useful to prototype and develop service and metadata standards. We are looking, especially through the EMBRACE project, to migrate to true Grid services, but like many other groups we are waiting for the long-anticipated merging of web and grid service standards. The EMBOSS project plans to expand in the coming few years to cover bioinformatics more generally, including genomics, protein structure, gene expression, proteomics, phylogenetics, genetics and biostatistics. This will require the participation of external groups to expand the project beyond its current EBI base, and we are actively seeking potential partners in each area. We will expect to build a service-based e-Science architecture around the applications and data resources through the EMBRACE project, with support and guidance from the community of users in academia and industry. The EMBRACE project will move beyond sequence data and analysis services to cover the remaining areas of the EBI’s core databases and to integrate services from our partners using the same standards and interfaces. Selected references Belhajjame, K. et al. (2008). Metadata management in the taverna workflow system. In ‘Proceedings CCGRID 2008 – 8th IEEE International Symposium on Cluster Computing and the Grid’, 651- 656 Lanzen, A. & Oinn, T. (2008). The Taverna Interaction Service: Enabling manual interaction in workflows. Bioinformatics, 2, 1118- 1120 Li, P. et al. (2008). Automated manipulation of systems biology models using libSBML within Taverna workflows. Bioinformatics, 2, 287-289 Li, P. et al. (2008). Performing statistical analyses on quantitative data in Taverna workflows: An example using R and maxdBrowse to identify differentially-expressed genes from microarray data. BMC Bioinformatics, 9, Article 33 82
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