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Guide to Malaria Pharmacology, GEMM 2019

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IUPHAR/MMV Guide to Malaria Pharmacology slide set presented by Dr. Jane Armstrong at GEMM 2019, Edinburgh, UK.

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Guide to Malaria Pharmacology, GEMM 2019

  1. 1. Introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY: an expertly curated resource capturing antimalarial compounds and their Plasmodium targets Jane Armstrong Wednesday 11th December 2019 Glasgow-Edinburgh Malaria Meeting
  2. 2. OVERVIEW • Project introduction • Database content • Navigating the website • Future plans
  4. 4. www.guidetomalariapharmacology.org • Medicines for Malaria Venture (MMV) funded project • Aims: • Extend the existing Guide to PHARMACOLOGY database (GtoPdb) with curated antimalarial compounds and their Plasmodium molecular targets • Provide a new portal that is optimized for the malaria research community Guide to MALARIA PHARMACOLOGY (GtoMPdb)
  5. 5. Data on human drug targets and potential targets Recommended experimental ligands Information on approved drugs Entry point into pharmacological literature Sources of further reading Detailed annotation for important targets Overviews of the key properties of target families Target and ligand nomenclature • The GtoPdb is an open, expert-driven database of pharmacological targets and the substances that act on them: ~1,700 drug targets, ~9,400 ligands, including ~1,300 approved drugs • Focus has been on the pharmacology of human non-infectious diseases • Data are reviewed by an international network of >500 scientists in >100 subcommittees of the IUPHAR Nomenclature Committee (NC-IUPHAR) IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb)
  7. 7. • All data are manually curated from the primary literature with guidance from our committee of scientific advisors • Steady growth in the number of antimalarial ligands and Plasmodium targets • Our most recent database release (2019.5) contains: • 72 ligands tagged as in GtoMPdb • 30 targets tagged as in GtoMPdb • Our curated ligands include antimalarial leads, drugs in preclinical and clinical development and approved medicines Content Expansion
  8. 8. GtoPdb:Target Name GtoPdb:Target Name PfATP4 PfPANK1 PfCARL PfPDEalpha PfCPSF3 PfPI3K PfCYTB PfPI4K PfDHFR-TS PfPKG PfDHODH PfPMX PfDXR Pfproteasome subunit beta type-5 PfeEF2 PfPNP PfGWT1 PfPPPK-DHPS PfHDAC1 PfSHMT PfHDP PfKRS1 PfHT PfcPheRS PfIspD PfPRS PfNDH2 PfThrRS PfNMT PfV-type proton ATPase Database Content – Target List
  9. 9. NAVIGATING THE WEBSITE Including key features
  10. 10. www.guidetomalariapharmacology.org • Retains the general layout of the parent site but includes a number of new features • Distinct identity with logo, colour scheme and header bar • Dedicated domain • Panels provide tailored routes for browsing antimalarial data: • Ligands • Targets • Parasite Lifecycle Stages • Target Species • The same categories can be accessed from the menu bar • Search (top right) is across GtoPdb and up- weights antimalarial data • New Help (under Resources) and About pages have been provided First public release (January 2019, beta v1) > Full public release and official launch (September 2019) GtoMPdb Portal
  11. 11. www.guidetomalariapharmacology.org/GRAC/LigandDisplayForward?ligandId=9721 • Modelled on GtoPdb Ligand page • Shows all curated information that our database holds about the ligand • New features have been developed for GtoMPdb ligands cipargamin (ID: 9721) GtoMPdb Ligand Page
  12. 12. cipargamin (ID: 9721) www.guidetomalariapharmacology.org/GRAC/LigandDisplayForward?ligandId=9721 • Additional curator comments of relevance to malaria • Target Candidate Profile (TCP) is provided where available • Information about Potential Target/Mechanism of Action. For antimalarials this is often unknown or poorly understood Malaria Tab GtoMPdb Ligand Page – new features
  13. 13. cipargamin (ID: 9721) www.guidetomalariapharmacology.org/GRAC/LigandDisplayForward?ligandId=9721 • A new whole organism assay type has been introduced to capture data from the whole cell assays used routinely in antimalarial drug discovery • This information is contained in the interactions table available on both the Ligand page and the Detailed Target Page Whole Parasite Assay Data GtoMPdb Ligand Page – new features
  14. 14. • Modelled on GtoPdb Detailed Target page • Shows all curated information that our database holds about the target • Includes links to PlasmoDB, UniProt and where available PDB • New comments section for information of particular relevance to malaria PfPNP (ID: 3077) www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3077 GtoMPdb Detailed Target Page
  15. 15. Homepage includes: • Background section with a short introduction to the Plasmodium lifecycle and links to more detailed resources • Links to individual page for each of the 5 top-level Plasmodium lifecycle stages Parasite Lifecycle Pages
  16. 16. Parasite Lifecycle Pages Individual Lifecycle Stage page
  17. 17. Parasite Lifecycle Pages Individual Lifecycle Stage page Section for detailed description of lifecycle stage Total number of target and ligand associations Table providing complete list of target and ligand interactions
  18. 18. Homepage includes: • Background section with a description of clinical and experimental relevant species • Links to individual pages for species that we have data for in GtoMPdb • Resources section Target Species Pages
  19. 19. Target Species Pages Individual Species page
  20. 20. Target Species Pages Individual Species page Section for detailed species description Total number of target and ligand associations Pop-up window provides strain information Table providing complete list of target and ligand interactions
  21. 21. FUTURE PLANS
  22. 22. Next steps… • Main development phase is now complete • Funding in place to maintain GtoMPdb and expand content • Curation of ligands will focus on compounds that are at an early stage of development • User feedback will be used to prioritize content expansion and inform improvements to the portal
  23. 23. • Poster session at GEMM2019 • Nucleic Acids Research (Database Issue): article describing current status The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY. Epub ahead of print: doi:10.1093/nar/gkz951 • Help page (https://www.guidetomalariapharmacology.org/malaria/gtmpHelpPage.jsp) • Blog posts (http://blog.guidetopharmacology.org/) • Follow us on • Download slides and posters • Email (enquiries@guidetopharmacology.org) @GuidetoPHARM Find out more about GtoMPdb
  24. 24. Acknowledgements • All past and current members of NC-IUPHAR • IUPHAR/MMV Expert Advisory Committee • Jeremy Burrows, Brice Campo, Javier Gamo, Stephen Ward (MMV) • Michael Spedding (IUPHAR) • Database team: • Jamie Davies (Principal Investigator) • Simon Harding and Joanna Sharman (Developers) • Adam Pawson, Elena Faccenda and Christopher Southan (Curators) • IUPHAR/MMV Guide to MALARIA PHARMACOLOGY and IUPHAR/BPS Guide to PHARMACOLOGY funders: