Approved drug and clinical target curation in the IUPHAR/BPS Guide to PHARMACOLOGY

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Presented by Helen E. Benson at Biocuration 2014, April 2014, Toronto The pace of recent pharmacological research has been matched by a movement towards data sharing and widening the availability of information on clinically-used compounds and their targets. The IUPHAR/BPS Guide to PHARMACOLOGY web portal is undergoing expansion to include curated information on all data-supported targets of approved drugs and their interacting ligands, in order to provide a user-friendly, searchable knowledgebase for the basic science of drug actions. The drug list now includes ~700 approved drugs (including antibodies and other biologicals), and 1050 INNs along with data on their primary targets including supporting quantitative interaction data (e.g. Ki, Kd, IC50). In addition we have made improvements to the website by clearly identifying approved drugs and primary targets and increasing the range of data provided. Ligand pages for approved drugs have been annotated with first approval dates, clinical use information and the molecular mechanism of action. Additional search functionality enables retrieval of implicated ligands and targets by disease name. Our curatorial starting point was based on intersects of drug and target lists, the results of which are now available on our website. Identifying primary targets can be difficult owing to lack of supporting published in vitro binding data for human targets. The number of primary targets of approved drugs is currently under debate in the literature; we are performing our own analysis and we will present our initial results. The Guide to PHARMACOLOGY complements existing resources by providing manually curated information on the pharmacological basis of drug action together with target and drug nomenclature, expert summaries, background reading and recommended compounds for experimental use. Future plans for expansion include the addition of information on compounds and targets undergoing clinical trials and further curation of target-disease mechanisms


1.2. Identifying consensus lists of approved drugs & targets 2. Curated information on approved drugs Helen E. Benson1, Elena Faccenda1, Christopher Southan1, Joanna L. Sharman1, Adam J. Pawson1, Michael Spedding2, Anthony J. Harmar1, Jamie Davies1 and NC-IUPHAR* 1The Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK. 2 Spedding Research Solutions SARL, 6 Rue Ampere, Le Vesinet, 78110, 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 IUPHAR/BPS Guide to PHARMACOLOGY Web portal is an open access resource providing overviews of the key properties, background reading and selective ligands of a wide range of biological targets. For selected targets, overview pages link to more detailed information including data on biological variants, tissue distribution, signalling mechanisms and pathophysiological role. The portal also provides access to the International Union of Basic and Clinical Pharmacology (IUPHAR) database, and links to the Concise Guide to PHARMACOLOGY 2013/2014, a publication snapshot created from the database overview pages and published in the British Journal of Pharmacology. Which drug target classes are covered? G protein-coupled receptors (GPCRs) including orphan GPCRs and adhesion GPCRs Voltage-gated ion channels (VGICs) Ligand-gated ion channels (LGICs) Other ion channels Nuclear hormone receptors Catalytic receptors Transporters Enzymes including peptidases and protein kinases Other protein targets Approved drug and clinical target curation in the IUPHAR/BPS Guide to PHARMACOLOGY We especially thank all contributors, collaborators and NC-IUPHAR members 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 the Concise Guide to PHARMACOLOGY. Our ligand list now includes a list of all the approved drugs in the database. These compounds also appear in lists by molecular class e.g. synthetic organics, peptides, antibodies. Recent developments The Guide to PHARMACOLOGY is being expanded to include: All data-supported primary targets of prescription drugs Targets of high research interest and clinical trial targets Drug clinical use and mechanism of action Quantitative data (typically IC50, Ki or Kd) supporting the link between a drug and its primary target Supported by: 4. Curation of information on approved drug targets Search by disease name Target pages include: Interaction tables with approved drug and primary target annotation. These tables can be ranked according to ligand name, species or affinity and are hyperlinked to ligand pages. Clinically relevant mutations and pathophysiology table with links to OMIM disease pages and rare disease database Orphanet It is now possible to search for targets and ligand by disease name. Some endogenous peptide ligands are also targets of approved drugs, e.g. the cytokine targets of antibodies. These entities are curated with interlinked target and ligand pages. To expand our coverage of clinical targets we have: Intersected and analysed publically available datasets to compile a consensus set of targets and approved drugs Identified the molecular mechanisms of action of approved drugs Developed stringent mapping criteria for curating primary targets of approved drugs Established correct molecular structures for drug active components Curated supporting quantitative data from literature Primary target identification and mapping We arrived at a consensus list of targets of approved drugs (TOADS) by comparing published target lists from the following sources: ChEMBL 17; DrugBank; The Therapeutic Target Database (TTD); Rask-Anderson M. et al. Annu Rev Pharmacol Toxicol. 2014; 54:9-26. Creating a list of approved drugs We compared sources (DrugBank, TTD, ChEMBL) within PubChem to identify a consensus list of approved drugs. Lists were merged and filtered to remove mixtures and low Mw structures. The results were then intersected with a Thompson Drugs of the Future list to identify additional drugs and with ~7000 INNs in PubChem to produce a 4-way corroborated list that will be expanded as the sources update. Results While our activity mappings encompass some polypharmacology, we have chosen to annotate minimal rather than maximal target sets. Our small-molecule figures are currently converging to ~250 human protein primary targets for ~1000 consensus chemical structures of approved drugs. The resulting target and ligand lists are available to download from our website. The clinical data tab includes a summary of the clinical use and the molecular mechanism of action. Curation of pharmacokinetic information for approved drugs is in progress. Approved drug pages include curated chemical structures and calculated physico-chemical properties. The summary tab for approved drugs now includes: Original FDA and/or EMA approval dates IUPAC name International Nonproprietary Name (INN) and number List of synonyms Database links to other relevant resources including DrugBank Function to search PubMed for clinical trials, titles and/or abstracts mentioning the drug.


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