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IUPHAR/MMV Guide to Malaria Pharmacology

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Poster on IUPHAR/MMV Guide to Malaria Pharmacology presented at BPS Pharmacology 2018 (London, Dec 2018).

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IUPHAR/MMV Guide to Malaria Pharmacology

  1. 1. J. F. Armstrong1, E. Faccenda1, A. J. Pawson1 , C. Southan1, S. D. Harding1, J. L. Sharman1, F. J. Gamo2,3, S. A. Ward4, B. Campo2, S.P.H. Alexander5, A.P. Davenport6, M. Spedding7, J. A. Davies1. Introduction Malaria is a major global health challenge with a disproportionate impact on resource-limited countries. In 2017, there were an estimated 219 million cases of the disease leading to 435,000 deaths worldwide, with over 90% of these cases occurring in the WHO Africa Region1. In the last decade there has been a dramatic improvement in the drug discovery pipeline for antimalarial medicines leading to an expansion of the global portfolio2. The IUPHAR/BPS Guide to Pharmacology (GtoPdb) has focused hitherto on the pharmacology and immunopharmacology associated with human non- infectious diseases3. We have recently been funded by Medicines for Malaria Venture (MMV) to curate antimalarial compounds and their Plasmodium molecular targets and to provide a new portal to the existing GtoPdb that is optimized for the malaria research community. The new resource, the IUPHAR/MMV Guide to Malaria Pharmacology (GtoMPdb), will be freely available, richly annotated and regularly updated. 1Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, University of Edinburgh, UK. 2 Medicines for Malaria Venture, ICC, 20 Route de Pré-Bois, PO Box 1826, 1215, Geneva, Switzerland. 3Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain. 4Centre for Drugs and Diagnostic Research, Liverpool School of Tropical Medicine, UK. 5School of Life Sciences, University of Nottingham Medical School, UK. 6Experimental Medicine and Immunotherapeutics, University of Cambridge, UK. 7Spedding Research Solutions SAS, Le Vésinet 78110, France. Introducing a new resource: the capture of drugs, leads and targets in the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY Methods The literature is mined to collect papers reporting antimalarial compounds. For database entries, papers are selected for expert curation when they have: • An explicit chemical structure • Quantitative potency for antimalarial activity in vitro • Activity data (where possible) against a purified Plasmodium target • in vivo and/or clinical data We map chemical structures to PubChem Compound Identifiers (CIDs) and assign UniProt IDs to evidence-supported Plasmodium target proteins. We have adapted our existing curational process to extract data required to fully describe the activity and target interactions of antimalarial compounds including: Plasmodium lifecycle activity of a compound and details of the Plasmodium species and isolate strain used during in vitro screening4,5. In addition a new “whole organism” assay type has been introduced to capture data from the whole cell assays used routinely in antimalarial drug discovery. GtoMPdb Data An initial set of antimalarial ligands and targets has been curated and is available in the GtoPdb (2018.4 release): these are accommodated within GtoPdb under a new classification of “Antimalarial ligands” (Ligands tab) and “Antimalarial targets” (Other protein targets tab). Targets: our intial curation effort includes nine Plasmodium molecular targets. Defining exact target sequences from information given by authors has proved difficult because less than 10% of Plasmodium proteins have been fully annotated by Swiss-Prot. Ligands: we use PubChem to resolve the structure of ligands curated from the literature. The internal entry for DSM421 below includes PDB link (right). Conclusions • We have successfully curated antimalarial mechanistic relationships into GtoMPdb • Continued curation will expand the number of available ligands and targets and will be guided by our IUPHAR/MMV expert advisory committee • The new portal will provide the malaria research community with lead structures, target sequences and efficacy data integrated across global efforts • Easy access and downloads will support chemical vendor matching, cross-screening for mechanistic investigations, target deconvolution, protein structure connectivity and homology-based cross-screening against other apicomplexan parasites Our submitted structures are retrievable via "guide to malaria pharmacology“ as a PubChem Substance (SID) query. From our 40 SIDs below: • 32 have active results in PubChem Bioassay • 37 have patent matches • 31 have vendor matches • One is unique to GtoPdb (ligand 10016; compound 55 [PMID: 29889526]) • 19 are tagged as “antimalarial” via other sources • 18 are approved drugs • The entries are linked to 108 PubMed papers • The structures are fully searchable in PubChem GtoMPdb Portal References 1. World Malaria Report 2018, https://www.who.int/malaria/publications/world-malaria-report-2018/en/ 2. MMV-supported projects, https://www.mmv.org/research-development/mmv-supported-projects 3. Harding SD, et al. (2018), Nucl. Acids Res. 46 (Issue D1): D1091-D1106, PMID: 29149325 4. Southan C, et al. (2018), ACS Omega 3(7), PMID: 30087946 5. www.slideshare.net/cdsouthan/the-iupharmmv-guide-to-malaria-pharmacology-103311134 Supported by: Public beta-release of GtoMPdb portal planned for January 2019 toprovidetailoredroutesintobrowsingthe antimalarialdata. The GtoMPdb portal homepage has been designed to provide tailored routes into browsing the antimalarial data toprovidetailoredroutesintobrowsingthe antimalarialdata. We have developed customised views of the data that include parasite lifecycle stage (an example page shown here) and target species activity