The document discusses updates on 5-HT2A receptor modulators since February 2018, covering the search for new small molecule compounds and the challenges in data extraction from various databases and literature. It highlights the limited yield of new potent antagonists and the necessity for automated alerts for new findings. The document emphasizes the need for collaborative sharing of annotations and searches for standardized cross-screening leads within the research community.

1. 5HT2A modulators in the wild:
updates since Feb 2018
Chris Southan, TW2Informatics, Göteborg
SAFER Symposium, SAROmics, Lund, Oct 2019
SAFER, European PhD Training Network to identify selective 5-HT2A receptor agonists
http://www.safer-itn.eu/

2. 2
Previous slides
https://www.slideshare.net/cdsouthan/5ht2a-modulators-in-gtopdb-and-other-databses

3. 3
Objectives and outline
o Look for new and potentialy useful human 5HT2A-directed small
molecule chemistry surfaced since the last meeting
o Check for compounds against as 5HT2A primary target but also
combined inhibitors
o Poll round the key databases, literature and patents
o Searching challenges arise from synonym soup, complex cross-
reactivities (see PMID 29679900) in vitro data gaps and in vivo
polypharmacology

4. 4
Polling the databases

5. 5
D- A- R - C- L- P
Relationship biocuration > high value databases
Document > assay > result > compound > location > 5HT2A
o Guide to Pharmacology (GtoPdb) ~ 1.2 ARCP curated per-paper
o ChEMBL ~ 14 per-paper
o BindingDB ~ 45 per-patent

6. 6
Statistics for key DARCP sources in PubChem
o Problem - no one extracts DARCP from new literature and patents
o ChEMBL has a curation time lag
o BindingDB curate US patents but some years after WO first-publications
o Guide to Pharmacology (GtoPdb) ~ 4 releases per year but focuses on clinical or
late development compounds rather than research leads
o Compounds claimed as ”novel” in papers have often been in PubChem for years
via automated patent extraction by SureChEMBL

7. 7
GtoPdb added 2 new P28223 ligands
o GtoPdb has 180 ligand entries across multiple
species
o These collapse to 135 distinct structures
o 18 are not in ChEMBL

8. 8
ChEMBL25: hum 5HT2A filtered by Ki potency
o Out of 6156 activity values 4,849 were Ki
o Useful distribution by pAct = pChEMBL
o Difficult to sort by date but no recent high-affinity compounds

9. 9
ChEMBL 23 vs 25
o Release 23 May 2017: 5763 compounds mapped to P28223
o Release 25 April 2019 : 6156
o In PubChem 25-23 = 978 CIDs
o 222 were novel in PubChem at release date
o 41 had additional submitters since the ChEMBL 25 release
o Only 3 of these had Bioassay data
o None of these were new 5HT2A primary data

10. 10
ChEMBL25: new 5HT2A-mapped compounds

11. 11
Polling the journals

12. 12
MeSH indicates proportionally flat publication rate
3022 hits
720 hits
311151 hits

13. 13
Synonym expansion increases hits but still flat

14. 14
Just bolt two antagonists together (March 2018)
o But no full specifcation of the bivalent structure in the paper
o No PubChem entries

15. 15
LSD derivatives
(Dec 2018)
o Ki vs [125I]DOI = 0.127 nM
o Usefully, the structures were mapped to
PubChem CIDs by the authors
o But as keywords not live links

16. 16
o CCN(C1CC1)C(=O)[C@H]2CN(C)[C@@H]3CC4=C[NH]C5=C4C(=CC=C5)C3=C2
o Surprisingly, PubChem –ve
More LSD derivatives (Feb 2019)

17. 17
Structure publication (Feb 2019)
o 5-HT2AR similar to 5-
HT2CR but unique side-
extended cavity near the
orthosteric binding site.
o Analogues of both ligands
pre-computed by
PubChem at 90%
Tanimoto
o Structures not novel but
could be useful

18. 18
Polling the patents

19. 19
Patent searching in SureChEMBL
• ~40 hits from 2018 plus 2019
• Most just mentions
• Very few true +ves of new SAR
• Always possible false negatives
(e.g. some A61-only)
• Commercial interest seems low

20. 20
WO2019183546
Treatment of diseases involving 5-HT2A receptor,
serotonin transporter (SERT) and/or pathways
involving dopamine D1/D2 receptor signalling systems
Organic Compounds, 2019-09-26
….reduced metabolic clearance of the tetra- deuterated
compound of Example 1 compared to its non-
deuterated counterpart, the compound of Formula Q….
o Unusually, deuterated lumateperone ADMET actually
reduced to practice (i.e. real data)
o d-4 Image not extracted by SureChEMBL so PubChem –ve

21. 21
WO2019162306
Antipsychotic and procognitive activity in one
molecule, acting by antagonism of 5-HT2A and 5-
HT6 receptors
Indole and benzimidazole derivatives as dual 5-HT2A
and 5-HT6 receptor antagonists 2019-08-29
o 33 = CN1CCN(CC1)C1=CC=CC2=C1C=C(N2CC1=CC=CS1)C(F)(F)F
o in vitro binding affinity as Ki in nM 5HT6 = 0.069, 5-HT2A = 0.17
o Many examples extracted but SCHEMBL21291611 was PubChem –ve Oct 2019

22. 22
Open annotation sharing
(a.k.a. getting the meat out of document hamburgers..)
o Can use Zotero for open publication sharing e.g. from my own library
o We can use a tag to indicate specific annotation of a PubChem CID or SMILES string that is not in the
document e.g. SAFER

23. 23
Conclusions
o Not a great yeild of new potent antagonists from public sources
o Literature and patents seem flat
o We should set up automated alerts
o Should take a look at ChEMBL 26 when it appears
o Some published activity on dual inhibitors
o We should make or source new leads for standardised cross-screening
o Document extractions now tagged in Zotero for sharing within the project team

24. 24
Endpiece
o https://sites.google.com/view/tw2informatics/home homepage
o https://europepmc.org/search?query=AUTH:%22Southan+C%22 publications

25. 25
Extras

26. 26
A useful Wikipedia page with links to structures

27. 27
Synonym soup
o Problematic for false +ves and
false -ves
o Makes it difficult to balance
specificity against recall for
literature and patent searches

28. 28
BindingDB SAR extraction from US patents
o 21 matches for HGNC:5293 in list at https://www.bindingdb.org/bind/ByPatent.jsp
o Two below include directed screens from Roche and Arena
o These 3000+ USPTOs are not recent patents but the full SAR sets have been curatorially
extracted and mapped to 240,000 PubChem CIDs

29. 29
ChEMBL25: 5HT2A target groupings by number of compounds