Presentation at the SAFER kick off meeting http://www.safer-itn.eu/

1. 5HT2A modulators in the IUPHAR/BPS Guide to
PHARMACOLOGY (GtoPdb), GPCRdb and other
bioactivity databases: so what's out there?
Christopher Southan
Representing the IUPHAR/BPS Guide to Pharmacology team, Deanery of Biomedical
Sciences, University of Edinburgh, UK.
1
Presentation for SAFER Symposium, University of Copenhagen, Feb 2018

2. Outline
• Brief intro to GtoPdb
• Overview of other sources of 5HT2A compounds
• Detailed look at four selected sources
• PubChem mappings
• Analysis tools
• Using these for comparisons
• Finding new ligands in papers and patents
• Discussion points and questions
2

3. Introducing GtoPdb
http://www.guidetopharmacology.org
• IUPHAR = International Union of Basic and Clinical Pharmacology, BPS = British
Pharmacological Society
• Formerly know as IUPHAR-DB for receptors and channels since 2003
• Since 2012 funded byWellcomeTrust to cover all targets in the human genome
• Since 2015 WellcomeTrust “fork” as Guide to IMMUNOPHARMACOLOGY
• Molecular mechanism of action (mmoa) mapping primary & secondary targets
• Release cycle time (with PubChem refreshes) down to ~ 2 months
• Described in six Nucleic Acids ResearchAnnual Database issues, latest as PMID
26464438 (2016) and PMID 29149325 (2018)
• Distilled into the 2-yearly BritishJournal of Pharmacology “Concise Guide to
PHARMACOLOGY” as a nine-paper series (see PMID 29055037) with outlinks
• Presents users with selected quality compounds for pharmacology research in
silico, in vitro, in cellulo, in vivo, and in clinic
• Collaborative contacts with many other dbs, includingGPCRdb and HGNC
3

4. 4
Quantitative core relationship capture with literature
provenance, expert-selected, curated and commented
Document > assay > result > compound > location > protein target
D- A- R - C- L- P

5. 5

6. So what is out there?
(5HT2A mappings + some mechanistic classification)
• GLIDA
• GLASS
• ChEMBL
• DrugBank
• GtoPdb
• Review articles
• GPCRdb
• OpenTargets
• TherapeuticTarget Database
• PDSP/Ki
• BindingDB
• Others?
6
• Only a few will be analysed here
• Main issue is identifying primary vs secondary
annotation (i.e. circularity)

7. GLIDA: is no more :(
7
• No longer populated
• But 2009 PubChem
entries still live
• Residual utility?
• Or trap for the unwary?
• 2007 paper still being
cited in 2017

8. 8
GPCRdb: 5HT2A ligand x species with data collation

9. GtoPdb: agonists and antagonists with cross-species data
9

10. GtoPdb 5HT2A: access to full ligand details
10
Extensive slicing, dicing and subsetting options, including PubChem CIDs

11. GtoPdb cross-reactivity data
11
• We curate cross-reactivity affinity data by target and species
• Can perform complex data slicing
• May find mechanistic shifts between species or between targets

12. Quetiapine: literature conflict between antagonist/agonist
12

13. DrugBank and UniProt chemistry x-refs
13

14. ChEMBL
14

15. ChEMBL: downloads
15
• Release 23 maps 5763 Chembl molecular IDs to 5HT2A, but not mechanistically
classified
• I scraped 37 IDs off the web page (previous slide) for approved and clinical candidates
with mechanistic classification (but provenancing of these is not entirely clear)

16. Mapping
tools (I)
16

17. Mapping
tools (II)
17
Note usual
round-
tripping
discrepancies
e.g. Only 83
of 87
DrugBank IDs
synonym-
map
Personal filters
Constitutive filters
Downloads
and sharing
Constitutive filters
Pivots

18. Mapping
tools (III)
18
• Good news: PubChem ID cross-mapping > Venn analysis works well
• Less good news: name > ID > structure specification round-tripping issues are constitutive
• Bad news: work is needed to understand inter-source divergence for 5HT2A modulators
and classifications thereof

19. Finding new ligands: PubMed > CitUlike > PubChem
Chemicalize (ChemAxon) > PubChem
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9825
3b is now curated into release 18.1 of GtoPdb

20. Finding new ligands: patent mining
20
• SureChEMBL
• Select: 5HT2A or
5-HT2A
• Patent
classification C07
• WO patents
(PCT)

21. Digging out the SAR
21

22. SureChEMBL > PubChem
22

23. Conclusions and discussion points
• The types of analyses described may be useful for SAFER
• Inter-source discordancies on 5HT2A data remain challenging
• Some could be followed up in silico
• However, direct standardised, reproducable experimental comparison is the
only definitve resolution of annotation discordancies
• The definition of 5HT2a ligand paramaters is complex (e.g. affinity
measurment, mechanistic classification, switching thereof, downstream
couplings, parologous and orthologous cross-reactivity
• Beyond clincal candidates, GtoPdb maybe the only source that curates the
mechanistic classification of modulators directly from the primary literature
• We need to be circumspect about the circularity of secondary public data (e.g.
the re-cycling of ChEMBL by other dbs)
23

24. Further info
24
Current Protocols in Bioinformatics, in press, March 2018