The IUPHARBPS Guide to PHARMACOLOGY anexpert-driven knowledgebase of drug targets andtheir ligandsAdam J Pawson1 Joanna L Sharman1 Helen E Benson1 Elena Faccenda1

Stephen PH Alexander2 O Peter Buneman3 Anthony P Davenport4

John C McGrath5 John A Peters6 Christopher Southan1 Michael Spedding7

Wenyuan Yu3 Anthony J Harmar1 and NC-IUPHAR

1The UniversityBHF Centre for Cardiovascular Science The Queenrsquos Medical Research Institute University ofEdinburgh Edinburgh EH16 4TJ UK 2School of Biomedical Sciences Life Sciences E Floor University ofNottingham Medical School Queenrsquos Medical Centre Nottingham NG7 2UH UK 3Laboratory for Foundationsof Computer Science School of Informatics 10 Crichton Street University of Edinburgh Edinburgh EH8 9ABUK 4Clinical Pharmacology Unit Level 6 Centre for Clinical Investigation Box 110 Addenbrookersquos HospitalUniversity of Cambridge Cambridge CB2 0QQ UK 5School of Life Sciences University of Glasgow GlasgowG12 8QQ UK 6Neuroscience Division Medical Education Institute Ninewells Hospital and Medical SchoolUniversity of Dundee Dundee DD1 9SY UK and 7Spedding Research Solutions SARL 6 Rue Ampere LeVesinet 78110 France

Received August 14 2013 Revised October 1 2013 Accepted October 24 2013

ABSTRACT

The International Union of Basic and ClinicalPharmacologyBritish Pharmacological Society(IUPHARBPS) Guide to PHARMACOLOGY (httpwwwguidetopharmacologyorg) is a new openaccess resource providing pharmacologicalchemical genetic functional and pathophysio-logical data on the targets of approved and experi-mental drugs Created under the auspices of theIUPHAR and the BPS the portal provides concisepeer-reviewed overviews of the key properties of awide range of established and potential drugtargets with in-depth information for a subset ofimportant targets The resource is the result ofcuration and integration of data from the IUPHARDatabase (IUPHAR-DB) and the published BPSlsquoGuide to Receptors and Channelsrsquo (GRAC) compen-dium The data are derived from a global network ofexpert contributors and the information is exten-sively linked to relevant databases includingChEMBL DrugBank Ensembl PubChem UniProtand PubMed Each of the 6000 small moleculeand peptide ligands is annotated with manuallycurated 2D chemical structures or amino acid

sequences nomenclature and database linksFuture expansion of the resource will complete thecoverage of all the targets of currently approveddrugs and future candidate targets alongside edu-cational resources to guide scientists and studentsin pharmacological principles and techniques

INTRODUCTION

Online resources have become indispensable tools forpharmacology and drug discovery in common withother disciplines in the biomedical sciences Databasessuch as ChEMBL (1) and PubChem (2) provide extensiveinformation on the bioactivity and chemical structures ofapproved and experimental drugs and their interactionwith targets either manually curated from the medicinalchemistry literature (ChEMBL) or uploaded by depositors(PubChem) To complement these large-scale resourcesthere is a need for an in-depth expert-curated overviewof the key targets and ligands to foster basic and clinicalresearch and innovative drug discovery and to educatethe next generation of researchers The InternationalUnion of Basic and Clinical PharmacologyBritish Phar-macological Society (IUPHARBPS) Guide toPHARMACOLOGY portal (httpwwwguidetopharmacologyorg) is being developed to assist research in

To whom correspondence should be addressed Tel +44 131 242 6693 Fax +44 131 242 6782 Email tonyharmaredacuk

The authors wish it to be known that in their opinion the first three authors should be regarded as Joint First authors

D1098ndashD1106 Nucleic Acids Research 2014 Vol 42 Database issue Published online 14 November 2013doi101093nargkt1143

The Author(s) 2013 Published by Oxford University PressThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (httpcreativecommonsorglicensesby30) whichpermits unrestricted reuse distribution and reproduction in any medium provided the original work is properly cited

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pharmacology drug discovery and chemical biology inacademia and industry by providing (i) an authoritativesynopsis of the complete landscape of current and researchdrug targets (ii) an accurate source of information on thebasic science underlying drug action (iii) guidance to re-searchers in selecting appropriate compounds for in vitroand in vivo experiments including commercially availablepharmacological tools for each target and (iv) anintegrated educational resource for researchers studentsand the interested public

The Guide to PHARMACOLOGY portal has beenonline since December 2011 The current release of thedatabase (October 2013) integrates two well-establishedsources The first of these is the IUPHAR Database[IUPHAR-DB (3)] which provides in-depth integrativeviews of the pharmacology genetics functions and patho-physiology of important target families including Gprotein-coupled receptors (GPCRs) ion channels andnuclear hormone receptors (NHRs) The second is theBPS lsquoGuide to Receptors and Channelsrsquo [GRAC (4)] acompendium previously published in print providingconcise overviews of the key properties of a wider rangeof targets than those covered in IUPHAR-DB togetherwith their endogenous ligands experimental drugsradiolabelled ligands and probe compounds with recom-mended reading lists for newcomers to each field

Management and peer review of the new resource is theresponsibility of the IUPHAR Committee on ReceptorNomenclature and Drug Classification (NC-IUPHAR)which acts as the scientific advisory and editorial boardThe organization has an international network of over 700expert volunteers organized into 60 subcommitteesdealing with individual target families The subcommitteemembers contribute expertize in several ways includingidentifying the key pharmacological properties of eachtarget along with quantitative activity data from theresearch literature NC-IUPHAR also directly supportsthe Guide to PHARMACOLOGY through its work inmonitoring lsquodeorphanizationrsquo of receptors (ie identifyingnew endogenous ligands) revising receptor nomenclaturein collaboration with HUGO Gene NomenclatureCommittee (HGNC) database (5ndash7) liaising withjournals and developing standards and terminology inquantitative pharmacology (8ndash10)

The primary sources of data in the Guide toPHARMACOLOGY are distinct from the medicinalchemistry and natural product literature extracted byChEMBL Our focus is on data and contextual informa-tion relevant to the preclinical phases of drug discoveryand includes extensive quantitative and chemical informa-tion manually curated from the primary research litera-ture predominantly from the leading non-specialistscientific journals and widely read specialist journals(Figure 1)

CONTENT AND DATA CURATION

The current version of the database includes pharmaco-logically relevant data and information on 2485 humantargets including GPCRs ion channels NHRs catalytic

(enzyme linked) receptors transporters and enzymes(including all protein kinases) (Table 1) Also includedis information on the genetics emerging pharmacologyfunctions and pathophysiology of 130 orphan GPCRs (7)Presently the resource describes the interactions

between target proteins and 6064 distinct ligand entities(Table 1) Ligands are listed against targets by their action(eg activator inhibitor) and also classified according tosubstance types and their status as approved drugsClasses include metabolites (a general category for allbiogenic non-peptide organic molecules includinglipids hormones and neurotransmitters) syntheticorganic chemicals (eg small molecule drugs) naturalproducts mammalian endogenous peptides syntheticand other peptides including toxins from non-mammalianorganisms antibodies inorganic substances and othernot readily classifiable compoundsThe new database was constructed by integrating data

from IUPHAR-DB (3) and the published GRAC compen-dium (4) An overview of the curation process is depictedas an organizational flow chart in Figure 2 New informa-tion was added to the existing relational database behindIUPHAR-DB and new webpages were created to displaythe integrated information For each new target informa-tion on human mouse and rat genes and proteinsincluding gene symbol full name location gene IDUniProt and Ensembl IDs was manually curated fromHGNC (5) the Mouse Genome Database (MGD) atMouse Genome Informatics (MGI) (11) the RatGenome Database (RGD) (12) UniProt (13) andEnsembl (14) respectively In addition lsquoOther namesrsquotarget-specific fields such as lsquoPrincipal transductionrsquo textfrom the lsquoOverviewrsquo and lsquoCommentsrsquo sections and refer-ence citations (downloaded from PubMed httpwwwncbinlmnihgovpubmed) were captured from GRACand uploaded into the database against a unique ObjectID For targets present in both IUPHAR-DB and GRACentries were cross-checked and merged A representativetarget family page is shown in Figure 3For the integration exercise all ligands listed in GRAC

were first checked against IUPHAR-DB using name-synonym- and structure-based comparisons For over1000 ligands there was an existing IUPHAR-DB entrythat matched The remaining new ligands (1900) werecurated using the workflow already established for thepopulation of IUPHAR-DB with ligand structures (15)An overview of the process is outlined belowInterrogation of multiple databases and direct literature

checks captured the correct structural information nomen-clature and target mapping for each ligand All small mol-ecules were resolved against a PubChem CompoundIdentifier (CID) as a primary molecular identifier and rep-resentative chemical structure (2) Each ligand was thenuploaded into the resource with a unique ID The quanti-tative pharmacological activity data of each ligand wascaptured from GRAC and uploadedLigands have individual pages (Figure 3) providing 2D

chemical structures or peptide sequences calculatedphysico-chemical properties classification and approvalstatus for human clinical use the International Union ofPure and Applied Chemistry (IUPAC) name and other

Nucleic Acids Research 2014 Vol 42 Database issue D1099

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names used as synonyms International NonproprietaryNames (INNs) are also currently provided for 730 com-pounds INNs are the official non-proprietary or genericnames given to pharmaceutical substances as designatedby the World Health Organization (WHO httpwwwwhointmedicinesservicesinnen) For small moleculessimplified molecular input line entry specification(SMILES) the IUPAC International Chemical Identifiers(InChI string and InChIKey) and Chemical AbstractsService (CAS) registry numbers (httpwwwcasorgindexhtml) are provided Peptides are specified by one-and three-letter amino acid sequences any post-transla-tional modifications and details of their protein precursorsLinks are provided to corresponding entries in relevantbioactivity and chemistry resources including BindingDB(16) Chemical Entities of Biological Interest (ChEBI) (17)ChEMBL (1) ChemSpider (18) DrugBank (19) HumanMetabolome Database (HMDB) (20) PharmGKB (21)RCSB Protein Data Bank (22) UniProt (13) and ZINC(23) Ligand pages also display a list of structurallysimilar ligands and a summary of all biological activitydata for each compound across all the targetsThe ligand page includes an option to display the results

for InChIKey searching in Google the utility of which hasrecently been described (24) While the entire Key is usedfor exact-match searches of ChemSpider the Googlesearch uses just the inner lsquolayerrsquo of 14 characters

approximating to the basic molecular connectivity Itwill thus retrieve all related entries with isomeric differ-ences encoded in the outer layer of the Key The resultstypically returned in lt05 s with very high specificity arethe matches from over 50 million InChIKeys cached byGoogle from a wide range of databases and web resources

IMPLEMENTATION

The data are held in a PostgreSQL relational database(httpwwwpostgresqlorg) with the exception of ligandstructures and physico-chemical properties which arestored in an Oracle database (Oracle CorporationRedwood Shores CA USA) Curators use custom-builtJava (Oracle Corporation Redwood Shores CA USA)software to enter and edit data The public web interface isimplemented using HTML CSS and JavaScript compo-nents generated dynamically on the server side by Javaservlets and Java Server Pages The web application runsin the Apache Tomcat servlet container (httptomcatapacheorg) on a Linux platform Ligand structure-based searching is implemented with the Pinpointchemical cartridge (Dotmatics Limited BishopsStortford UK) and chemical structure editing capabilityis provided by the MarvinSketch chemical editor(ChemAxon Limited Budapest Hungary) Ligandchemical structure formats and identifiers were generated

Figure 1 Breakdown of scientific journals cited in the resource The chart shows the top 20 most cited journals in the resource and the contributionof each journal as a percentage of the total

D1100 Nucleic Acids Research 2014 Vol 42 Database issue

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using the Open Babel software (25) IUPAC names weregenerated using JChem for Excel (ChemAxon LimitedBudapest Hungary) and physico-chemical propertieswere generated using the Chemistry Development Kit(26) Ligand images were created using the NCICADDChemical Identifier Resolver from the National CancerInstitute (httpcactusncinihgovchemicalstructure)Small molecule ligands with similar structures were clus-tered using Pipeline Pilot (Accelrys San Diego CA USA)and peptides with similar sequences were clustered usingh-cd-hit part of the CD-HIT Suite (27)

WEB INTERFACE

Users can access lsquoTargetrsquo and lsquoLigandrsquo lists and searchtools directly from the portal homepage as well as fromthe navigation bar at the top of every subsequentwebpage Each class of target (eg transportersenzymes) is listed according to protein family (eg ATP-binding cassette family amino acid hydroxylases) Theportal is designed to provide users with access to twoviews of pharmacologically relevant data on the targetsin the database The organization and content of thesetwo complementary views is described below

(1) Users are initially presented with concise searchableoverviews of the properties of each family of targetsData on all members of a target family or subfam-ily are presented on a single webpage (Figure 3) The

page for each target family includes a brief overviewof the properties of the target group Details areprovided on approved nomenclature (where applic-able approved by NC-IUPHAR) and synonymshuman mouse and rat gene names and links to theHGNC MGD RGD Ensembl and UniProt data-bases Quantitative data are provided on recom-mended ligands classified by their mode of action(eg agonists antagonists substrates inhibitors andradiolabelled ligands) and other information specificto the class of target (eg the signal transductionmechanisms used by GPCRs or the biophysicalproperties of ion channels) Overall the data focuson human proteins and include only key pharmaco-logical agents chosen because they are likely to bethe most useful in the laboratory (ie they are select-ive and available by donation or from commercialsources) A list of review articles recommended asfurther reading key references and additional com-mentary (highlighting for example where species dif-ferences or ligand metabolism are potentialconfounding factors) are also provided These pagesare designed to serve as an introduction to a familyof targets and are a useful entry point into the lit-erature for newcomers to a particular field

(2) From the family overview pages users can then navi-gate (via the lsquoMore detailed pagersquo links see Figure 3)to database pages with more in-depth informationfor a subset of important targets providingexpanded views of the pharmacology genetics func-tions and pathophysiology These include a longerintroduction to the family and separate pagesproviding a comprehensive description of eachtarget and its function with information on proteinstructure ligand interactions signalling mechanismstissue distribution functional assays and biologicallyimportant variants (eg single nucleotide polymorph-isms and splice variants) Reported ligand inter-actions may include endogenous ligands currentand historical licensed and experimental drugs andavailable radiolabelled ligands along with informa-tion on their actions (eg agonist allosteric modula-tor inhibitor) and quantitative data where possiblefrom multiple literature sources Comparative datafor mouse and rat species are also listed Inaddition the phenotypes resulting from altered geneexpression (eg in genetically altered animals or inhuman genetic disorders) are described An extensiveset of links is provided to other resources includingprotein gene structure disease and drug target data-bases Family-specific information and database linksare also provided such as Enzyme Commission (EC)numbers and links to the KEGG BRITE hierarchydescribing enzymatic reactions (28) For furtherdetails on the types of information that areprovided in the detailed view see previous publica-tions (31529)

All literature citations in both views are linked toPubMed and all ligand entries are linked to individualligand pages providing additional information (as

Table 1 Database statistics

Target class Number of targets

7TM receptors 400GPCRs including orphans 394Orphan GPCRs 130Other 7TM proteins 6Nuclear hormone receptors 48Catalytic receptors 223Ligand-gated ion channels 84Voltage-gated ion channels 142Other ion channels 49Enzymes 1008Transporters 503Other protein targets 28Total number of targets 2485

Chemical class Number of ligands

Synthetic organics 3504Metabolites 550Endogenous peptides 687Other peptides including synthetic peptides 1089Natural products 161Antibodies 10Inorganics 55Others 8Approved drugs 559Withdrawn drugs 11Drugs with INNs 857Radioactive ligands 550Total number of ligands 6064

Number of synonyms 51189Number of binding constants 41076Number of references 21774

Nucleic Acids Research 2014 Vol 42 Database issue D1101

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described in the section on lsquoCONTENT AND DATACURATIONrsquo above)The interface includes a simple search box where users

can enter keywords such as ligand or target names andadvanced search tools which allow searches by specific

database field database identifier (eg Ensembl ID)chemical identifier (eg standard InChIKey CASregistry number) or PubMed identifier Chemical structuresearches can also be performed by providing a structure inSMILES format or drawing a chemical structure using

Figure 2 The Guide to PHARMACOLOGY curation process and organizational chart

D1102 Nucleic Acids Research 2014 Vol 42 Database issue

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Figure 3 Screenshot of the Cannabinoid receptor family page in the Guide to PHARMACOLOGY with overlaying screenshots of a typical ligandpage and reference page with link-out to PubMed Also shown is a link to the lsquoMore detailed pagersquo of the CB1 receptor with a screenshot of the topsection of the target page showing the lsquoContentsrsquo table listing the types of information available for this target

Nucleic Acids Research 2014 Vol 42 Database issue D1103

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the structure editor The search tool can perform exactmatch substructure similarity and SMARTS-patternsearches (httpwwwdaylightcomdayhtmldoctheorytheorysmartshtml) The chemical structure editor is alsoaccessible from ligand pages clicking on the ligand imageloads the structure into the editor where it can be modifiedand used to search the database Search results indicatewhich database fields matched the query term and linksare provided to the relevant database entriesExtensive help pages and a tutorial on how to use the

resource are also provided The help page can be accessedvia linked icons within database fields as well as from thenavigation menu and home page The help page includesdefinitions of terms used to describe the data displayed onthe site in addition to providing a detailed guide to usingthe various search functions

COMPARISON WITH OTHER RESOURCES

There are other databases that have a degree of conceptualand content overlap with the Guide to PHA-RMACOLOGY some of which are included in thisissue Of these ChEMBL DrugBank and TherapeuticTarget Database (TTD) (30) are the closest Howeverthe Guide to PHARMACOLOGY differs from these re-sources in a number of important ways Firstly we restrictthe range of protein targets and ligands to those mostrelevant to therapeutics and drug discovery chosen withthe exercise of curatorial judgement and backed by ournetwork of experts with a focus on the quality anddepth of annotation Secondly this is subject to reviewand quality control not only by our international expertcommittee members operating as a de facto network oflsquosuper-curatorsrsquo but also via user feedback Thirdly wecurate activity data for research compounds from primaryliterature sources including posters and patents ratherthan from review articles with a focus on the interactionsof each compound with its data-supported primary target(eg Angiotensin-converting enzyme (ACE) for captopril)Fourthly the data can be annotated with free-textcomments that would otherwise not easily fit intodatabase schema These include information on alterna-tive isomers and salt forms An example here are the eightapproved drugndashprodrug pairs for ACE inhibitors thatpresent a particular curatorial challenge (eg seehttpwwwguidetopharmacologyorgGRACLigandDis-playForwardligandId=6352) These 16 structures are notboth explicitly linked and activity-mapped in otherdatabasesAnother example that illustrates the differences between

the three databases is atorvastatin In the Guide toPHARMACOLOGY (httpwwwguidetopharmacologyorgGRACLigandDisplayForwardtab=biologyampligan-dId=2949) there are three activity mappings between thisligand and the primary drug target hydrox-ymethylglutaryl-CoA reductase (HMGCR) with both aKi (14 nM) and an IC50 for human (8 nM) together withan IC50 for rat (116 nM) The equivalent DrugBank entry(DB01076) is mapped to 3 targets 11 enzymes and 9 trans-porters but these include associations from the literature

that are not all supported by directly measured molecularinteractions The ChEMBL entry (CHEMBL1487) isassay-mapped to 117 proteins and lists 217 IC50 valuesincluding proteins in the DRUGMATRIX screen andsome antimalarial parasite results There are four IC50

values for the rat and three for the human enzyme In com-parison the two literature references for atorvastatin inTTD are not the same as from the other three sourcesMapping differences between ChEMBL DrugBank andTTD have previously been explored in detail (2431) butthe overall picture between these and the Guide toPHARMACOLOGY is one of complementarity We thussuggest that pharmacologically oriented users might findthe curatorially selected set of stringent activity mappingsin the Guide to PHARMACOLOGY a simpler entry point(indeed we designed it with this in mind) but we provideextensive linking to the other high-value resources

SUMMARY AND FUTURE DIRECTIONS

Our goal is to complete a stringently curated directmapping (where the primary literature data permits)between chemical structures and their primary moleculartargets initially for targets of approved drugs but extend-ing this to clinical and research targets Published listingsand the exact definitions for these categories vary widelybut indicate a range of 200ndash300 for the former and500ndash1000 for the latter (32ndash36) Possible reasons fordisparities in these numbers are indicated in databasecomparison reports (2431) We are also in the processof updating our ligand structure submissions toPubChem facilitating UniProt cross references for theirtargets and reviewing new information sources forpossible inclusion

The creation of the new portal reflects our intention todevelop the resource into a comprehensive online guidewhich will include educational resources and to produce alsquoConcise Guide to PHARMACOLOGYrsquo to be publishedin PDF format at two yearly intervals as a supplement tothe British Journal of Pharmacology The lsquoConcise Guideto PHARMACOLOGYrsquo which replaces GRAC will be abiennial snapshot of succinct overviews of the propertiesof each target family intended to be a quick desktop ref-erence guide Additionally this will provide a permanentrecord (DOI digital object identifier) that will survivedatabase updates and therefore allow the precise contextof the database to be understood at any time in the future(37)

Since the Guide to PHARMACOLOGY portal now in-tegrates data from the printed GRAC compendium andIUPHAR-DB we are planning a phased retirement ofIUPHAR-DB The current URL (httpwwwiuphar-dborg) will remain active with appropriate notices directingusers to the Guide to PHARMACOLOGY portal

DATA ACCESS

The Guide to PHARMACOLOGY is available online athttpwwwguidetopharmacologyorg The websiteincludes downloadable files containing current receptor

D1104 Nucleic Acids Research 2014 Vol 42 Database issue

Downloaded from httpsacademicoupcomnararticle-abstract42D1D10981053678by gueston 05 April 2018

the structure editor The search tool can perform exactmatch substructure similarity and SMARTS-patternsearches (httpwwwdaylightcomdayhtmldoctheorytheorysmartshtml) The chemical structure editor is alsoaccessible from ligand pages clicking on the ligand imageloads the structure into the editor where it can be modifiedand used to search the database Search results indicatewhich database fields matched the query term and linksare provided to the relevant database entriesExtensive help pages and a tutorial on how to use the

resource are also provided The help page can be accessedvia linked icons within database fields as well as from thenavigation menu and home page The help page includesdefinitions of terms used to describe the data displayed onthe site in addition to providing a detailed guide to usingthe various search functions

COMPARISON WITH OTHER RESOURCES

There are other databases that have a degree of conceptualand content overlap with the Guide to PHA-RMACOLOGY some of which are included in thisissue Of these ChEMBL DrugBank and TherapeuticTarget Database (TTD) (30) are the closest Howeverthe Guide to PHARMACOLOGY differs from these re-sources in a number of important ways Firstly we restrictthe range of protein targets and ligands to those mostrelevant to therapeutics and drug discovery chosen withthe exercise of curatorial judgement and backed by ournetwork of experts with a focus on the quality anddepth of annotation Secondly this is subject to reviewand quality control not only by our international expertcommittee members operating as a de facto network oflsquosuper-curatorsrsquo but also via user feedback Thirdly wecurate activity data for research compounds from primaryliterature sources including posters and patents ratherthan from review articles with a focus on the interactionsof each compound with its data-supported primary target(eg Angiotensin-converting enzyme (ACE) for captopril)Fourthly the data can be annotated with free-textcomments that would otherwise not easily fit intodatabase schema These include information on alterna-tive isomers and salt forms An example here are the eightapproved drugndashprodrug pairs for ACE inhibitors thatpresent a particular curatorial challenge (eg seehttpwwwguidetopharmacologyorgGRACLigandDis-playForwardligandId=6352) These 16 structures are notboth explicitly linked and activity-mapped in otherdatabasesAnother example that illustrates the differences between

the three databases is atorvastatin In the Guide toPHARMACOLOGY (httpwwwguidetopharmacologyorgGRACLigandDisplayForwardtab=biologyampligan-dId=2949) there are three activity mappings between thisligand and the primary drug target hydrox-ymethylglutaryl-CoA reductase (HMGCR) with both aKi (14 nM) and an IC50 for human (8 nM) together withan IC50 for rat (116 nM) The equivalent DrugBank entry(DB01076) is mapped to 3 targets 11 enzymes and 9 trans-porters but these include associations from the literature

that are not all supported by directly measured molecularinteractions The ChEMBL entry (CHEMBL1487) isassay-mapped to 117 proteins and lists 217 IC50 valuesincluding proteins in the DRUGMATRIX screen andsome antimalarial parasite results There are four IC50

values for the rat and three for the human enzyme In com-parison the two literature references for atorvastatin inTTD are not the same as from the other three sourcesMapping differences between ChEMBL DrugBank andTTD have previously been explored in detail (2431) butthe overall picture between these and the Guide toPHARMACOLOGY is one of complementarity We thussuggest that pharmacologically oriented users might findthe curatorially selected set of stringent activity mappingsin the Guide to PHARMACOLOGY a simpler entry point(indeed we designed it with this in mind) but we provideextensive linking to the other high-value resources

SUMMARY AND FUTURE DIRECTIONS

Our goal is to complete a stringently curated directmapping (where the primary literature data permits)between chemical structures and their primary moleculartargets initially for targets of approved drugs but extend-ing this to clinical and research targets Published listingsand the exact definitions for these categories vary widelybut indicate a range of 200ndash300 for the former and500ndash1000 for the latter (32ndash36) Possible reasons fordisparities in these numbers are indicated in databasecomparison reports (2431) We are also in the processof updating our ligand structure submissions toPubChem facilitating UniProt cross references for theirtargets and reviewing new information sources forpossible inclusion

The creation of the new portal reflects our intention todevelop the resource into a comprehensive online guidewhich will include educational resources and to produce alsquoConcise Guide to PHARMACOLOGYrsquo to be publishedin PDF format at two yearly intervals as a supplement tothe British Journal of Pharmacology The lsquoConcise Guideto PHARMACOLOGYrsquo which replaces GRAC will be abiennial snapshot of succinct overviews of the propertiesof each target family intended to be a quick desktop ref-erence guide Additionally this will provide a permanentrecord (DOI digital object identifier) that will survivedatabase updates and therefore allow the precise contextof the database to be understood at any time in the future(37)

Since the Guide to PHARMACOLOGY portal now in-tegrates data from the printed GRAC compendium andIUPHAR-DB we are planning a phased retirement ofIUPHAR-DB The current URL (httpwwwiuphar-dborg) will remain active with appropriate notices directingusers to the Guide to PHARMACOLOGY portal

DATA ACCESS

The Guide to PHARMACOLOGY is available online athttpwwwguidetopharmacologyorg The websiteincludes downloadable files containing current receptor

D1104 Nucleic Acids Research 2014 Vol 42 Database issue

Downloaded from httpsacademicoupcomnararticle-abstract42D1D10981053678by gueston 05 April 2018

and channel lists NC-IUPHAR nomenclature synonymsgenetic information HGNC gene nomenclature and iden-tifiers and other database accessions Other file formatsare available by emailing enquiriesguidetopharma-cologyorg Information on linking to Guide toPHARMACOLOGY pages is provided at httpwwwguidetopharmacologyorglinkingjsp To further facilitateexternal programmatic and user access to the database weare developing an application programming interface(API) and Web services This will allow our content tobe exploited in new integration initiatives such as OpenPHACTS (38) of which we are already an associatemember The database is licensed under the Open DataCommons Open Database License (ODbL) (httpopendatacommonsorglicensesodbl) and its contentsare licensed under the Creative Commons Attribution-ShareAlike 30 Unported license (httpcreativecommonsorglicensesby-sa30)

CITING THE RESOURCE

For a general citation of the resource we recommendciting this article Citation formats for specific targetpages are provided on the website

ACKNOWLEDGEMENTS

The authors thank all the GRAC consultants (a full list ofconsultants for the Fifth Edition of GRAC can be foundat httponlinelibrarywileycomdoi101111j1476-5381201101649_2xfull) The authors thank all members ofNC-IUPHAR and its global network of subcommitteesfor their ongoing support NC-IUPHAR membersSPH Alexander TI Bonner WA Catterall AChristopoulos AP Davenport CT Dollery S EnnaD Fabbro AJ Harmar K Kaibuchi Y Kanai VLaudet RR Neubig EH Ohlstein JA Peters JPPin U Ruegg P du Souich M Spedding and MWWright The work of NC-IUPHAR is supported by theAmerican Society for Pharmacology and ExperimentalTherapeutics Servier GlaxoSmithKline Pfizer ActelionAstraZeneca DiscoveRx Abbott and Merck MilliporeThe authors also acknowledge the support of the BritishHeart Foundation Centre of Research Excellence Award(RE08001)

FUNDING

International Union of Basic and Clinical PharmacologyBritish Pharmacological Society Wellcome Trust [099156Z12Z] Funding for open access charge Wellcome Trust

Conflict of interest statement None declared

REFERENCES

1 GaultonA BellisLJ BentoAP ChambersJ DaviesMHerseyA LightY McGlincheyS MichalovichDAl-LazikaniB et al (2012) ChEMBL a large-scale bioactivitydatabase for drug discovery Nucleic Acids Res 40D1100ndashD1107

2 BoltonE WangY ThiessenPA and BryantSH (2008)PubChem integrated platform of small molecules and biologicalactivities In WheelerRA and WangDC (eds) Annual Reportsin Computational Chemistry Vol 4 American Chemical SocietyWashington DC pp 217ndash241

3 SharmanJL BensonHE PawsonAJ LukitoVMpamhangaCP BombailV DavenportAP PetersJASpeddingM and HarmarAJ (2013) IUPHAR-DB updateddatabase content and new features Nucleic Acids Res 41D1083ndashD1088

4 AlexanderSP MathieA and PetersJA (2011) Guide toreceptors and channels (GRAC) 5th edn Br J Pharmacol164(Suppl 1) S1ndashS324

5 GrayKA DaughertyLC GordonSM SealRLWrightMW and BrufordEA (2013) Genenamesorg theHGNC resources in 2013 Nucleic Acids Res 41 D545ndashD552

6 ChunJ HlaT LynchKR SpiegelS and MoolenaarWH(2010) International Union of Basic and Clinical PharmacologyLXXVIII Lysophospholipid receptor nomenclature PharmacolRev 62 579ndash587

7 DavenportAP AlexanderSP SharmanJL PawsonAJBensonHE MonaghanAE LiewWC MpamhangaCPBonnerTI NeubigRR et al (2013) International Union ofBasic and Clinical Pharmacology LXXXVIII G protein-coupledreceptor list recommendations for new pairings with cognateligands Pharmacol Rev 65 967ndash986

8 NeubigRR SpeddingM KenakinT and ChristopoulosA(2003) International Union of Pharmacology Committee onReceptor Nomenclature and Drug Classification XXXVIIIUpdate on terms and symbols in quantitative pharmacologyPharmacol Rev 55 597ndash606

9 PinJP NeubigR BouvierM DeviL FilizolaM JavitchJALohseMJ MilliganG PalczewskiK ParmentierM et al(2007) International Union of Basic and Clinical PharmacologyLXVII Recommendations for the recognition and nomenclatureof G protein-coupled receptor heteromultimers Pharmacol Rev59 5ndash13

10 KenakinT (2013) New concepts in pharmacological efficacy at7TM receptors IUPHAR review 2 Br J Pharmacol 168554ndash575

11 EppigJT BlakeJA BultCJ KadinJA and RichardsonJE(2012) The Mouse Genome Database (MGD) comprehensiveresource for genetics and genomics of the laboratory mouseNucleic Acids Res 40 D881ndashD886

12 LaulederkindSJ HaymanGT WangSJ SmithJRLowryTF NigamR PetriV de PonsJ DwinellMRShimoyamaM et al (2013) The Rat Genome Database2013ndashdata tools and users Brief Bioinform 14 520ndash526

13 UniProt Consortium (2013) Update on activities at the UniversalProtein Resource (UniProt) in 2013 Nucleic Acids Res 41D43ndashD47

14 FlicekP AhmedI AmodeMR BarrellD BealK BrentSCarvalho-SilvaD ClaphamP CoatesG FairleyS et al (2013)Ensembl 2013 Nucleic Acids Res 41 D48ndashD55

15 SharmanJL MpamhangaCP SpeddingM GermainPStaelsB DacquetC LaudetV and HarmarAJ (2011)IUPHAR-DB new receptors and tools for easy searching andvisualization of pharmacological data Nucleic Acids Res 39D534ndashD538

16 LiuT LinY WenX JorissenRN and GilsonMK (2007)BindingDB a web-accessible database of experimentallydetermined protein-ligand binding affinities Nucleic Acids Res35 D198ndashD201

17 de MatosP AlcantaraR DekkerA EnnisM HastingsJHaugK SpiteriI TurnerS and SteinbeckC (2010) ChemicalEntities of Biological Interest an update Nucleic Acids Res 38D249ndashD254

18 PenceHE and WilliamsA (2010) ChemSpider an onlinechemical information resource J Chem Educ 87 1123ndash1124

19 KnoxC LawV JewisonT LiuP LyS FrolkisA PonABancoK MakC NeveuV et al (2011) DrugBank 30 acomprehensive resource for lsquoomicsrsquo research on drugs NucleicAcids Res 39 D1035ndashD1041

Nucleic Acids Research 2014 Vol 42 Database issue D1105

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20 WishartDS KnoxC GuoAC EisnerR YoungNGautamB HauDD PsychogiosN DongE BouatraS et al(2009) HMDB a knowledgebase for the human metabolomeNucleic Acids Res 37 D603ndashD610

21 McDonaghEM Whirl-CarrilloM GartenY AltmanRB andKleinTE (2011) From pharmacogenomic knowledge acquisitionto clinical applications the PharmGKB as a clinicalpharmacogenomic biomarker resource Biomark Med 5795ndash806

22 BermanHM WestbrookJ FengZ GillilandG BhatTNWeissigH ShindyalovIN and BournePE (2000) The ProteinData Bank Nucleic Acids Res 28 235ndash242

23 IrwinJJ SterlingT MysingerMM BolstadES andColemanRG (2012) ZINC a free tool to discover chemistry forbiology J Chem Inf Model 52 1757ndash1768

24 SouthanC SitzmannM and MuresanS (2013) Comparing thechemical structure and protein content of ChEMBL DrugBankHuman Metabolome Database and the Therapeutic TargetDatabase Mol Inform (in press)

25 OrsquoBoyleNM BanckM JamesCA MorleyCVandermeerschT and HutchisonGR (2011) Open Babel anopen chemical toolbox J Cheminform 3 33

26 SteinbeckC HoppeC KuhnS FlorisM GuhaR andWillighagenEL (2006) Recent developments of the chemistrydevelopment kit (CDK) ndash an open-source java library for chemo-and bioinformatics Curr Pharm Des 12 2111ndash2120

27 HuangY NiuB GaoY FuL and LiW (2010) CD-HITSuite a web server for clustering and comparing biologicalsequences Bioinformatics 26 680ndash682

28 KanehisaM GotoS SatoY FurumichiM and TanabeM(2012) KEGG for integration and interpretation of large-scalemolecular data sets Nucleic Acids Res 40 D109ndashD114

29 HarmarAJ HillsRA RosserEM JonesM BunemanOPDunbarDR GreenhillSD HaleVA SharmanJLBonnerTI et al (2009) IUPHAR-DB the IUPHAR database of

G protein-coupled receptors and ion channels Nucleic Acids Res37 D680ndashD685

30 ZhuF ShiZ QinC TaoL LiuX XuF ZhangL SongYZhangJ HanB et al (2012) Therapeutic target database update2012 a resource for facilitating target-oriented drug discoveryNucleic Acids Res 40 D1128ndashD1136

31 MuresanS SitzmannM and SouthanC (2012) Mappingbetween databases of compounds and protein targets MethodsMol Biol 910 145ndash164

32 OveringtonJP Al-LazikaniB and HopkinsAL (2006)How many drug targets are there Nat Rev Drug Discov 5993ndash996

33 Rask-AndersenM AlmenMS and SchiothHB (2011) Trendsin the exploitation of novel drug targets Nat Rev Drug Discov10 579ndash590

34 SouthanC BoppanaK JagarlapudiSA and MuresanS (2011)Analysis of in vitro bioactivity data extracted from drugdiscovery literature and patents ranking 1654 human proteintargets by assayed compounds and molecular scaffolds JCheminform 3 14

35 AgarwalP SanseauP and CardonLR (2013) Novelty in thetarget landscape of the pharmaceutical industry Nat Rev DrugDiscov 12 575ndash576

36 Rask-AndersenM MasuramS and SchiothHB (2014) Thedruggable genome evaluation of drug targets in clinical trialssuggests major shifts in molecular class and indication Ann RevPharmacol Toxicol 54 (in press)

37 NIS Organization (2013) Recommended Practices for OnlineSupplemental Journal Article Materials NISO RP-15-2013Baltimore MD

38 WilliamsAJ HarlandL GrothP PettiferS ChichesterCWillighagenEL EveloCT BlombergN EckerG GobleCet al (2012) Open PHACTS semantic interoperability for drugdiscovery Drug Discov Today 17 1188ndash1198

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