Presentation for World Congress of Pharmacology, Kyoto, July 2018

1. Capturing drugs, leads and targets in the
IUPHAR/MMV Guide to Malaria Pharmacology
C. Southan1, J. F. Armstrong1, E. Faccenda1, S. D. Harding1, J. L.
Sharman1, A. J. Pawson1, J Gamo2,3 B Campo2, J. A. Davies1
M. Spedding4, S.P.H. Alexander4
1) IUPHAR/BPS Guide to Pharmacology, Centre for Discovery Brain Sciences, University of
Edinburgh, UK., 2) Medicines for Malaria Venture, Geneva, Switzerland, 3) Tres Cantos
Medicines Development Campus, GlaxoSmithKline, Spain, 4) International Union of Basic &
Clinical Pharmacology (IUPHAR)
1
World Congress of Pharmacology, Kyoto, Global Infectious Diseases session,
Wednesday, July 4, 2018

2. Abstract (will not be presented)
Introduction: GtoPdb has been traditionally focused on the pharmacology associated with non-infectious
diseases. However, in October of 2017 we initiated a collaboration with Medicines for MalariaVenture (MMV) in
Geneva, where we have been piloting the curation of antimalarial compounds and Plasmodium targets for
approved drugs and the global portfolio of new clinical candidates and research leads .This will provide explicit
mappings between compounds and targets for current and new antimalarials.
Methods:The main method is mining primary literature, review articles to collate an open CiteUlike tagged
collection . For database entries, drugs and leads are prioritised for having a) specific chemical structure, b) a
reported potency for antimalarial activity in vitro and, where possible c) activity data against the purified
Plasmodium target and d) in vivo/ clinical data. We map chemical structures to PubChemCompound Identifiers
(CIDs) and assign Plasmodium target proteins to UniProt accession numbers. These are accommodated within
GtoPdb under a new classification of “antinfective targets”
Results: We have successfully adapted GtoPdb data model for Plasmodium target mapping. However, sub-
species and strain isolates may produce equivocality as to the exact sequence targeted. Whilst some
publications are from open drug discovery practitioners, we can map most lead compounds to their
corresponding patents via SureChEMBL. We can also accommodate lead structures with unknown mechanisms
of parasite killing. Our first curated leads have been submitted to PubChem (e.g. SID 340590277 against N-
Myristoyltransferase, UniProt Q8ILW6)
Conclusion We have curated antimalarial relationship mappings into GtoPdb and surfaced these in our public
release. We are now expanding to triage more publications. Our initiative enhances the facility with which the
antimalarial community can access lead, target and efficacy data integrated between disparate global R&D
efforts.This will support reciprocal cross-screening of leads for mechanistic investigations, target
deconvolution, 3D structures and homology-based cross-screening directed against apicomplexan parasites.
2

3. Overview of Guide to PHARMACOLOGY (GtoPdb)
expert curated relationships
(PMID 29149325 and poster PO2-8-11)
• Total number of ligands = 9251
• Ligands with PubChem chemical structure entries (C) = 7070
• PubMed IDs associated with these by us (D) = 8109
• Human targets with quantitative interactions (P) = 1467
• Number of curated binding constants (R) = 15851
• Data from release 2018.2 http://www.guidetopharmacology.org/about.jsp
3
Document > assay > result > compound > location > protein target
D- A- R - C- L- P

4. Motivation for establishing the IUPHAR/MMV
Guide to Malaria Pharmacology (GtoMPdb)
• Engagement by MMV, their collaborators and many research teams globaly,
some with an Open Source Drug Discovery modus operandi, has accelerated
the generation of new antimalarial leads and clinical candidates
• However, finding links between publications, code names, chemical structures,
activity data and molecular mechanisms of action (mmoa), (including
Plasmodium target sequences) is challenging
• It remains an anachronism that neither authors nor journals submit chemical
structures, code names or target associations of new antimalarials to databases
• These “lost linkages” have problematic consequences, e.g. hindering data-
mining, exchange of compounds for cross-screening, omics profiling and
deconvolution of unknown mmoa
• The GtoPdb data model has already proved flexible in its adaptation to the
Guide to Immunopharmacology and pilot studies indicated that curated
antimalarial relationships could also be accomodated
4

5. Using CiteUlike for open pre-curation
5

6. Database example for OSM-S-38
6

7. Portal
alpha
release
7

8. Liver stage examples
8

9. Ligand listing
9

10. Ligand matches to PubChem entries
• All 28 curated ligands so far
• We will submit these, including
future novels
• They will get PubMed links for our
references
• Query “Guide to Malaria
Pharmacology” will retrieve our
submissions
• 22 are ”Rule of 5”
• 4 are not in ChEMBL
• 26 have SureChEMBL patent
extraction matches
• Only 15 are tagged ”Antimalarials”
in PubChem
• 14 have vendor matches
• Some do not have the code
numbers we have matched (but
will when we submit)
10

11. Data-supported targets vs unknown mmoa
11
Target proteins with direct binding data, strong genetic inference or cell screening
evidence
From the current 28 ligands the mechanistic target evidence: unknown mmoa is ~ 2:1
(but this is shifting as curation proceeds)

12. Achievments and plans
• Adapting the GtoPdb schema and expert curation approaches to antimalarial
compounds and targets has been sucessful
• We hope this systematic ”global portfolio” capture will contribute to progress
• The first set of records wil go live in GtoPdb release ~July 2018 and then be
submitted to PubChem
• Develpment of the Alpha portal is progressing via feedback from MMV, a
constituted Expert Commitee and initial users
• Some malaria-specific challenges still need optimisation, e.g. separating
IC50 potency for parasite killing in vivo from inhibition IC50 against purified
targets in vitro
• CiteUlike capture and curation of mechanistic papers
• The comunity can alert us to new antimalarial lead papers (e.g. use our open
CiteUlike tags)
• Consider pre-publication capture (e.g. Sydney Open Source Malaria team)
• Check for patents with new SAR not yet in journals 12

13. Questions
and further
info
https://cdsouthan.blogspot.com/2017/08/name
-to-struc-resolution-for-yet.html?q=antimalarial