GtoPdb teaching slides
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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.
![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 ]
39](https://image.slidesharecdn.com/gtopdbteachingslidesjan2017-170423132958/85/GtoPdb-teaching-slides-39-320.jpg)
![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
40](https://image.slidesharecdn.com/gtopdbteachingslidesjan2017-170423132958/85/GtoPdb-teaching-slides-40-320.jpg)
![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”
48](https://image.slidesharecdn.com/gtopdbteachingslidesjan2017-170423132958/85/GtoPdb-teaching-slides-48-320.jpg)
GtoPdb teaching slides
- 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 1
- 2. Outline • Straw polls • Database content • Navigation and searching • Tasks for you • Feedback on navigability • The atorvastatin naming story 2
- 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? 3
- 4. Spread of approved drug numbers 4
- 5. New approved drugs: a bad year 5
- 7. DATABASE CONTENT For release 2016.4 Nov 2016 7
- 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 8
- 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 9
- 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 10
- 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 11
- 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 12
- 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 13
- 14. NAVIGATING THE WEBSITE AND SEARCH TOOLS 14
- 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 15
- 16. Home Page 16
- 17. 17
- 18. Histamine receptors family summary page 18
- 19. Histamine H2 receptor concise summary view 19
- 20. Reference information and linkout to PubMed 20
- 21. Link to more details for the H2 receptor 21
- 22. H2 receptor detailed annotation page 22
- 23. Linkouts to other gene and protein resources 23
- 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 24
- 25. Ligand page for the approved drug ranitidine 25
- 26. Biological activity data for ranitidine at targets in the database 26
- 27. Clinical use and mechanism of action for ranitidine 27
- 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 28
- 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 29
- 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 30
- 31. Target search tools • Search by name or keyword, identifier (e.g. UniProtKB accession) or reference (e.g. PubMed id) 31
- 32. Ligand search tools • Search by name, identifier (e.g. PubChem CID, InChI) or structure (exact match, similarity, substructure, SMARTS) 32
- 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 33
- 34. TASKS 34
- 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? 35
- 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? 36
- 38. Which Drug Did You Mean? 38
- 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 ] 39
- 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 40
- 41. What isAtorvastatin? - for patients and doctors 41 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 42
- 43. What is atorvastatin? – Google images 43
- 44. Pharmacological activity in vivo is ~70% active metabolites CID 9851106 CID 9808225 CID 60823 44
- 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 45
- 46. Salt confusion (II): what gets to patients CID 53252956 CID 656846 No INNs, USANs or clinical trials entries for these salts 46
- 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 47
- 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” 48
- 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 49
- 50. Caduet: an approved combination http://clinicaltrials.gov/ct2/show/NCT01107743 Drugbank Wikipedia 50
- 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). 51
- 52. END NOTES 52
- 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 55
Editor's Notes
- #16: You may wish to switch to a live demo here. The following slides can be used in place of a demo.