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Presented by Helen Benson at the 6th International Biocuration Conference, Cambridge UK, April 2013. Enzymes constitute a significant proportion of the druggable genome. In order to fully exploit their potential as drug targets it is vital that database tools exist to provide easily-navigable access to relevant genetic, biochemical and pharmacological information. The Guide to PHARMACOLOGY portal (http://www.guidetopharmacology.org/) is an open access resource providing expert-curated information on human drug targets and the substances that act on them. We have recently expanded the information available on enzyme drug targets, including the addition of >500 protein kinases and quantitative data on their interactions with 72 approved drugs and experimental inhibitors. The resource includes information on enzyme nomenclature, substrates, reactions, cofactors, inhibitors, links to relevant external resources and references, and expert overviews of their functions and (patho)physiology. For a subset of important targets we provide detailed expert-curated summaries from the primary literature on a wide range of properties. A pilot study to investigate the data types that needed to be added to the database for enzymes as drug targets involved curation of the enzymes of the lanosterol biosynthesis pathway, which includes the target of statin drugs used to treat hypercholesterolemia. This work formed a template for the curation of other enzymes such as the kinases, and is continuously adapted as new enzyme targets and data types are added. The Guide to PHARMACOLOGY now includes >1050 distinct enzymes, adding to existing information on >1200 receptors, ion channels and transporter proteins. This marks a significant milestone in our mission to provide expert-curated information for all the targets of current prescription medicines and other likely targets of future small molecule drugs via the Guide to PHARMACOLOGY portal. This is a unique resource which should appeal to scientists from a range of disciplines and aid further exploration of enzymes as drug targets.
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3. DiscoveRx KINOMEscan® screening data
2. Curated information on enzymes
Helen E. Benson1, Elena Faccenda1, Joanna L. Sharman1, Adam J. Pawson1, Doriano Fabbro2, Daniel K. Treiber3, Stephen P.H. Alexander4, Michael Spedding5, Anthony J. Harmar1 and NC-IUPHAR*1The University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, UK. 2 Piqur Therapeutics, Hohe Winde Strasse 120, CH-4059 Basel, Switzerland. 3KINOMEscan Division of Discoverx Corporation, 11180 Roselle St., San Diego, California 92121, United States. 4 School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK. 5 Les laboratoires Servier, 50 Rue Carnot, Suresnes 92284, France. * The International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification.
1. About the ‘Guide to PHARMACOLOGY’
What is the Guide to PHARMACOLOGY?The Guide to PHARMACOLOGY web portal is an open access resource providing general overviews of the key properties, publications and selective ligands of a wide range of biological targets, accessed via the British Pharmacological Society Guide to Receptors and Channels (GRAC) database. The portal also provides access to the International Union of Basic and Clinical Pharmacology (IUPHAR) database, a freely available, online resource with detailed, expert-curated information on several important classes of human drug targets and their ligands.
Which drug targets are covered?• G protein-coupled receptors (GPCRs),
including Orphan GPCRs andAdhesion GPCRs
• Voltage-gated ion channels (VGICs)• Ligand-gated ion channels (LGICs)• Other ion channels• Nuclear hormone receptors• Catalytic receptors• Transporters• Enzymes, including all protein
kinases
www.guidetopharmacology.org www.iuphar-db.org
Enzymes as drug targets: curated pharmacological information
in the ‘Guide to PHARMACOLOGY’[email protected]
Supported by:
We especially thank all contributors, collaborators and NC-IUPHAR members
Figure 1. Examples of various enzyme database tables
What kinds of data are provided about drug targets?• Comprehensive information on nomenclature, structure,
genomics, physiological function, tissue distribution, functional assays, biologically significant variants, pathophysiology, transduction mechanisms, ion conductance, heteromeric complexes and more.
• Pharmacological information includes the affinities of selected ligands and drugs, including potent and selective agonists, antagonists, modulators and pore blockers, as well as radiolabelled ligands.
• Useful links are provided to important resources including PubMed, Entrez Gene, RefSeq, human, rat and mouse genome databases, Wikipedia, the Protein Data Bank (PDB).
Where do the data come from?All data are curated from the primary literature by an international network of >700 experts coordinated by the IUPHAR Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) and the Editors of GRAC.
What kind of information is provided?• All kinases are organised into the main hierarchical groups, families and
subfamilies.• Genomic information, official gene and protein nomenclature, and previous
and unofficial nomenclature.• Extensive links to external databases, including information on post-
translational modifications in PhosphoSitePlus®, substrates in the Human Protein Reference Database, and 3D structures in PDB.
What kinds of data are provided?• Affinity data for 72 kinase inhibitors across
456 kinases, including clinically relevant mutants, lipid, and atypical kinases.
• Structural information on all the ligands, ligand synonyms, Approved drug status, International Nonproprietary Names (INNs), and external chemistry related database links.
Additional features under development• Corresponding DiscoveRx TREEspot™ Profile
images.• Cellular data on clinically relevant kinases.• Information on kinase inhibitors; mechanism
of action, clinical use, ADME (absorption, distribution, metabolism, and excretion), approvals and indications, adverse effects.
• Additional biochemical screening datasets.Figure 2. Examples of screening
datasets and inhibitor ligand pages 4. Future Directions
• The Guide to PHARMACOLOGY is being expanded to include all targets of prescription drugs, and targets of research interest for the development of future drugs, many of which are enzymes.
• The portal will provide succinct information on each target, with links to pages providing detailed information on a selected set of targets.
• Starting with ~20 registered kinase inhibitors, curated clinical information on all approved drugs on the Guide to PHARMACOLOGY will be added to the resource.
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