抄録
Introduction: GtoPdb has been traditionally focused on the pharmacology associated with non-infectious diseases [1]. However, in October of 2017 we initiated a collaboration with Medicines for Malaria Venture (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 [2]. 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 [3]. 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 PubChem Compound Identifiers (CIDs) and assign Plasmodium target proteins to UniProt accession numbers. These are accommodated within GtoPdb under a new classification of antinfective targets [4]
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 SurChEMBL. 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 other apicomplexan parasites.
References:
[1] Harding et al. (2018). Nucl. Acids Res. 45 (Database Issue), doi: 10.1093/nar/gkx1121.
[2] Philips et al. (2017) Nat Rev Dis Primers. 3:17050
[3] http://www.citeulike.org/user/cdsouthan/tag/antimalarial_targets
[4] http://guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=970
