Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads

Kasper Jensen, Damian Rafal Plichta, Gianni Panagiotou, Irene Kouskoumvekaki

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Abstract

The parasite Plasmodium falciparum is the main agent responsible for malaria. In this study, we exploited a recently published chemical library from GlaxoSmithKline (GSK) that had previously been confirmed to inhibit parasite growth of the wild type (3D7) and the multi-drug resistance (D2d) strains, in order to uncover the weak links in the proteome of the parasite. We predicted 293 proteins of P. falciparum, including the six out of the seven verified targets for P. falciparum malaria treatment, as targets of 4645 GSK active compounds. Furthermore, we prioritized druggable targets, based on a number of factors, such as essentiality for growth, lack of homology with human proteins, and availability of experimental data on ligand activity with a non-human homologue of a parasite protein. We have additionally prioritized predicted ligands based on their polypharmacology profile, with focus on validated essential proteins and the effect of their perturbations on the metabolic network of P. falciparum, as well as indication of drug resistance emergence. Finally, we predict potential off-target effects on the human host with associations to cancer, neurological and dermatological disorders, based on integration of available chemical-protein and protein-protein interaction data. Our work suggests that a large number of the P. falciparum proteome is potentially druggable and could therefore serve as novel drug targets in the fight against malaria. At the same time, prioritized compounds from the GSK library could serve as lead compounds to medicinal chemists for further optimization.
Original languageEnglish
JournalMolecular BioSystems
Volume8
Issue number6
Pages (from-to)1678-1685
ISSN1742-206X
DOIs
Publication statusPublished - 2012

Keywords

  • genome
  • growth inhibition
  • metabolic network
  • multi-drug resistance
  • polypharmacology profile
  • cancer Neoplasms (MeSH) neoplastic disease
  • dermatological disorder integumentary system disease
  • malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease
  • neurological disorder nervous system disease
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common host
  • Protozoa Invertebrata Animalia (Animals, Invertebrates, Microorganisms, Protozoans) - Sporozoa [35400] Plasmodium falciparum species parasite strain-D2d
  • proteins drug target
  • 10060, Biochemistry studies - General
  • 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 18506, Integumentary system - Pathology
  • 20506, Nervous system - Pathology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 60502, Parasitology - General
  • 60504, Parasitology - Medical
  • 64002, Invertebrata: comparative, experimental morphology, physiology and pathology - Protozoa
  • Transport and Circulation
  • Biochemistry and Molecular Biophysics
  • Blood and Lymphatics
  • Parasitology

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