Download - GtoPdb teaching slides
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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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Outline
• Straw polls
• Database content
• Navigation and searching
• Tasks for you
• Feedback on navigability
• The atorvastatin naming story
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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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Spread of approved drug numbers
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New approved drugs: a bad year
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Clinical development numbers
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DATABASE CONTENT
For release 2016.4 Nov 2016
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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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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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• 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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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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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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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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NAVIGATING THE WEBSITE
AND SEARCH TOOLS
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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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Home
Page
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Histamine receptors family summary page
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Histamine H2 receptor concise summary view
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Reference information and linkout to PubMed
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Link to more details for the H2 receptor
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H2 receptor detailed annotation page
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Linkouts to other gene and protein resources
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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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Ligand page for the approved drug
ranitidine
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Biological activity data for ranitidine at targets in the database
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Clinical use and mechanism of action for ranitidine
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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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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 receptorisopentenyl-diphosphate Δ-isomerase 1
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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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Target search tools
• Search by name or keyword, identifier (e.g. UniProtKB
accession) or reference (e.g. PubMed id)
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Ligand search tools
• Search by name, identifier (e.g. PubChem CID, InChI) or
structure (exact match, similarity, substructure, SMARTS)
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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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TASKS
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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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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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ATORVASTATIN NAMING
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Which Drug Did
You Mean?
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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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History of Atorvastatin
• 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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What is Atorvastatin? - for patients and doctors
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FDA insert label:
hemi-calcium trihydrate
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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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What is atorvastatin? – Google images
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Pharmacological activity in vivo is ~70% active metabolites
CID 9851106
CID 9808225
CID 60823
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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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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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• 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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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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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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Caduet: an approved combination
http://clinicaltrials.gov/ct2/show/NCT01107743
Drugbank Wikipedia
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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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END NOTES
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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:
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References
PubMed 26464438
PubMed 26650438 (this is the intro to a series of articles)
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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
@GuidetoPHARM
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