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

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:

References

PubMed 26464438

PubMed 26650438 (this is the intro to a series of articles)

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suggestions

enquiries@guidetopharmacology.org

@GuidetoPHARM

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