The document is an outline for a presentation on the IUPHAR/BPS Guide to Pharmacology database. It provides an overview of the database content including over 2700 drug targets and nearly 9000 ligands and drugs. It describes how users can navigate the database to find information on targets, ligands, and their interactions. The presentation also highlights some example searches and tasks for users to find information on the drug atorvastatin, such as its molecular weight, target, approved generics, and clinical trials. It ends with acknowledging contributions to building and maintaining the database.

1. www.guidetopharmacology.org
The IUPHAR/BPS Guide to
PHARMACOLOGY (GtoPdb)
Chris Southan (on behalf of the GtoPdb team)
Jan 2017, Edinburgh University
http://www.guidetopharmacology.org
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2. Outline
• Straw polls
• Database content
• Navigation and searching
• Tasks for you
• Feedback on navigability
• The atorvastatin naming story
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3. Straw poll – show of hands please for:
• Cheminformatics or
bioinformatics background
• BNF
• FDA, EMA
• INN, USAN, stems
• PubChem
• UniProt/Swiss-Prot
• Boolean queries
• Disease-causing protein
variants
• How many prescription
drugs are there?
• How many were
approved in 2016?
• How many new drugs
are in Phase III?
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4. Spread of approved drug numbers
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5. New approved drugs: a bad year
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6. Clinical development numbers
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7. DATABASE CONTENT
For release 2016.4 Nov 2016
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8. GtoPdb content - targets
>2700 established or potential drug targets and related
proteins:
• G protein-coupled receptors (Class A, B, C, frizzled, adhesion and
orphan GPCRs)
• Ligand-gated ion channels
• Voltage-gated ion channels
• Other ion channels
• Nuclear hormone receptors
• Catalytic receptors
• Kinases
• Proteases
• Other enzymes
• Transporters
• Other protein targets
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9. Approaching 9000 ligands and drugs:
• Approved drugs
• Synthetic organic compounds
• Metabolites, hormones, neurotransmitters
• Natural products
• Endogenous peptides
• Other peptides
• Inorganics
• Antibodies
• Labelled ligands
GtoPdb content - ligands
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10. • We have 14,701 curated interactions
• These are between 2,794 human targets and 8,675 ligands.
• For 1,429 human targets we have recorded quantitative
interactions to a ligand (mostly IC50, Ki or Kd)
• In PubChem, the 8,625 ligands generate 6565 compound
identifiers for small molecules and peptides
• The 2,110 SIDs that do not merge into CIDs are antibodies,
small proteins and large peptides
GtoPdb content - relationships
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11. Concise target family summaries
• Concise target family summaries introducing the main
properties
• Expert overviews and comments
• Selective ligands, clinicically-used drugs, endogenous
ligands and probes (radioligands and PET ligands where
available)
• Further reading lists
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12. Detailed annotation for selected targets
Data are collected and reviewed by NC-IUPHAR
subcommittees and individual experts:
• Gene and protein information
• IUPHAR nomenclature and synonyms
• Extensive pharmacology: agonist, antagonist and allosteric
regulator affinities, ion channel blockers, enzyme/transporter
inhibitors and substrates
• Signal transduction mechanisms; Tissue distribution
• Functional assays; Physiological functions
• Mouse gene knockout phenotypes
• Clinically-relevant mutations and pathophysiology
• Gene expression changes in disease; biologically significant
variants
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13. Other features
• Extensively referenced and linked to primary literature in
PubMed
• Focus is on human data but where species differences
exist or literature data unavailable other species are given
• Linked to corresponding entries in other resources, e.g.
UniProt, Ensembl, Entrez Gene, KEGG, OMIM, ChEMBL
• Ligand information including structure, peptide
sequences, clinical data and nomenclature, linked up to
chemistry resources including PubChem
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14. NAVIGATING THE WEBSITE
AND SEARCH TOOLS
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15. Navigating GtoPdb
• Browse lists of targets and ligands
• Target families are listed under expandable family trees
• Target information is presented in two levels of detail
1. Concise family summary pages
2. Detailed pages for selected targets
• Ligand pages are provided for all compounds in GtoPdb
• Use the search tools to search by name, keyword,
identifier or ligand structure
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16. Home
Page
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17. 
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18. 
Histamine receptors family summary page
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19. Histamine H2 receptor concise summary view
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20. 
Reference information and linkout to PubMed
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21. 
Link to more details for the H2 receptor
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22. 
H2 receptor detailed annotation page
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23. Linkouts to other gene and protein resources
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24. Click for species-specific selectivity table
Ligand is endogenous in this species
Ligand is labelled
Ligand is radioactive
Approved drug
Primary target of this compound

Interaction tables
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25. Ligand page for the approved drug
ranitidine
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26. 
Biological activity data for ranitidine at targets in the database
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27. 
Clinical use and mechanism of action for ranitidine
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28. Peptide ligand information
• Curated sequence
information
• Post-translational and
chemical group
modifications
• Precursor proteins and
encoding genes
• Similar sequences
Ligand page for the endogenous
peptide endothelin-1
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29. Bespoke tables for different targets
• Heteromeric complexes: subunit composition
• GPCRs: signal transduction mechanism
• Ion channels: ion conductance and voltage-dependence
• Nuclear receptors: DNA co-binding partners, target genes
• Enzymes: substrates, cofactors, reaction mechanisms
• Transporters: substrates
GABAB receptor
isopentenyl-diphosphate Δ-isomerase 1
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30. Database search functionality
• Quick search box at the top of every page with
autocomplete for target, family and ligand names
• Advanced searches are available on the Target Search
and Ligand Search pages
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31. Target search tools
• Search by name or keyword, identifier (e.g. UniProtKB
accession) or reference (e.g. PubMed id)
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32. Ligand search tools
• Search by name, identifier (e.g. PubChem CID, InChI) or
structure (exact match, similarity, substructure, SMARTS)
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33. Advanced search by keyword
• Keyword searches, for example by disease name, can
facilitate retrieval of associated ligands and targets
A search for “Alzheimer’s
disease” returns implicated
targets and ligands tested
in clinical trials
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34. TASKS
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35. Tasks 1
• Find atorvastatin – what’s the parent molecular weight
• What is the target name and SwissProt ID?
• How many approved statins are there?
• How many unapproved statins?
• What is the weakest inhibitor listed?
• Why was this made and tested?
• How many clinical trials were published involving
atorvastatin in 2015?
• Can you find any metabolites?
• What different ways can you find them?
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36. Tasks II
• How many entries come back when you search
“atorvastatin” in PubChem Compound?
• Why and when did this drug go “generic”? (not in Guide)
• Which external source was authentic and useful for this
information?
• What other non-statin drugs for hypercholesterolemia can
be found in the Guide?
• Which of these appears to be a major breakthrough as
new mechanism of action and was approved in 2015? (in
Guide but not obvious)
• Does anyone have a BNF Medicines Complete
password?
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37. ATORVASTATIN NAMING
37

38. Which Drug Did
You Mean?
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39. History of Drug Names
Approximate timelines
[cpd registration system structure and ID------------------------------------------------------------]
[patent IUPAC or image--------------------------------------------------------------------]
[internal code name(s) externally blinded-------]
[code name(s) > structure declared externally -----]
[journal papers -----------------------------------------------------------------------]
[International Non-proprietary name INN]
[INN indexed in MeSH-----------------]
[USAN, BAN, JAN --------------------]
[brand name(s)-------------------]
[combination brand ]
[genric name/brand ]
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40. History ofAtorvastatin
• 1985: (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-
1-yl]-3,5-dihydroxyheptanoic acid IUPAC
• ~ 1987: Park-Davis internal code number CI-981
• ~ 1995: Atorvastatin [INN:BAN] Atorvastatin calcium [USAN], Atorvastatin calcium
trihydrate [INN] Atorvastatina (Spain)
• 1997 Lipitor (brand name) Faboxim (Argentina) Zurinel (Chile) etc
• 2004: Caduet (brand name) Norvasc (amlodipine besylate) and Lipitor(atorvastatin
calcium)
• 2012: atorvastatin calcium – generic - Ranbaxy
• 2012: amlodipine besylate and atorvastatin calcium – generic - Ranbaxy
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41. What isAtorvastatin? - for patients and doctors
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FDA insert label:
hemi-calcium trihydrate

42. What is atorvastatin? – for informaticians
PubChem CID 60823
Wikepedia
ChemSpider 54810
DrugBank APRD00055
CHEMBL1487
CAS 134523-00-5
PubChem submissions include:
(3R,5R) CID 60823
(5R) CID 51052072
(3R) CID 21029434
(3S,5R) CID 6093359
(3S,5S) CID 62976
No stereo CID 2250
Fully deuterated CID 53234038
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43. What is atorvastatin? – Google images
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44. Pharmacological activity in vivo is ~70% active metabolites
CID 9851106
CID 9808225
CID 60823
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45. Salt confusion (I) atorvastatin calcium
CID 60822 Mw 1155
CAS 134523-03-8
CID 656846 Mw 1209
CAS 344423-98-9
CID 11227182 Mw 598
INN = atorvastatin
USAN/BAN = atorvastatin
calcium
FDA packege
insert lable
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46. Salt confusion (II): what gets to patients
CID 53252956
CID 656846
No INNs, USANs or clinical trials entries for these salts
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47. • Tautomer/stereo mutiplexing and structure interconversion differences (e.g.
complex antibiotics)
• Popular structures > 100s of submitters > many vendors > more noise
• Opaque ecosystem of primary submitters, secondary linkers, declared circularity,
cryptic circularity, and submitters having independent portals with different rules
• Older drugs accumulate 100’s of synonyms and database x-refs, with erros
• Accumulated wet assay results are dependent on how long the drug has been in
which public screening collection
• Deprecated structures not always refreshed between databases globally
• Pro-drugs, metabolites or tested combinations rarely have explicit x-refs
Causes of drug linkage spaghetti
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48. Mixtures: problematic all round
• Atorvastatin parent (CID 60823) has 379 mixture SIDs and 147 mixture CIDs
permuatated from 122 component CIDs
• Of the 122 components 58 have a MeSH pharmacology tag, 92 have
BioAssays results, 70 are in DrugBank, 101 are in ChEMBL, and 47 are below
200 mw (and thus probably salts not drugs)
• Of the 147 mixture CIDs, only the 2 atorvastatin dimers have assay results or
pharmacology so none of the drug mixtures have direct data links
• None are in DrugBank CIDs and only atorvastin calcium is in ChEMBL
• 138 of the 147 have been extracted from patents by Derwent/Thomson and are
unlikely to get data links
• The small number of important drug combinations that do have data and/or trial
results are difficult to identify
• Tested drug mixtures rarely get public code names, some get trade names but
never INNs
• Chemistry rules may split mixtures and synonyms in databases
• PubMed "Drug Combinations"[MeSH Term] = 54,186 but no SID or CID links
• Mixture components can be designated with space, / , + or ”co”
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49. The famous polypill
CID 44602839 Thomson Pharma
18 clinicaltrials.gov entries, but
only partial component links
aspirin 81 mg, enalapril 2.5 mg, atorvastatin 20 mg and hydrochlorothiazide 12.5 mg
(polypill) PMID: 21647425: Australian New Zealand Clinical Trials Registry
ACTRN12607000099426
DrugBank and TTD negative
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50. Caduet: an approved combination
http://clinicaltrials.gov/ct2/show/NCT01107743
Drugbank Wikipedia
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51. Summary
• You can navigate the linkage spaghetti in name, synonym, structure
bioactivity and mixture space, but this needs perspicacity and
circumspection.
• The current drug information ecosystem with multiple stakeholders seems
destined to remain ”fuzzy”
• Beyond informatics challenges the consequences, particularly from frank
errors, could be more serious
• WHO INNs and naming stems play a key positive role – but ;
• No open athoritative database - only 7000 PDF entries
• No transparent coordination between USAN, FDA, MeSH, national offices, or
clinical trials registries
• Susceptable to commercial flanking tactics
• Fixed drug combinations have a bright pharmacological future but a difficult
informatics one
• The fuzz includes scientific challenges (e.g. complex strucutures, dynamic
tautomerism, active metabolites, formulation differences, paucity of
standardised and comparable activity data).
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52. END NOTES
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53. Acknowledgements
• The late Prof Tony Harmar, founder and original PI
• Michael Spedding, Steve Alexander, Ian McGrath, Anthony Davenport, John
Peters and all past and present members of NC-IUPHAR
• NC-IUPHAR subcommittees and Concise Guide to PHARMACOLOGY
contributors
• Database team:
• Prof. Jamie Davies (Principal Investigator) Joanna Sharman , Simon Harding
(Developers), Adam Pawson, Elena Faccenda and Christopher Southan (Curators),
Toni Wigglesworth (Project Administration)
• Database team alumni
• IUPHAR/BPS Guide to PHARMACOLOGY funders:

54. References
PubMed 26464438
PubMed 26650438 (this is the intro to a series of articles)

55. Stay in touch
• NC-IUPHAR and GtoPdb team newsletter
• Receive email alerts for new content and news items
• Follow us on
• Download slides and posters
• Email us with any questions, comments,
suggestions
enquiries@guidetopharmacology.org
@GuidetoPHARM
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