Journal article
Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads
Department of Systems Biology, Technical University of Denmark1
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark2
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark3
CFB - Metagenomic Systems Biology, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark4
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.
| Language: | English |
|---|---|
| Year: | 2012 |
| Pages: | 1678-1685 |
| ISSN: | 17422051 and 1742206x |
| Types: | Journal article |
| DOI: | 10.1039/c2mb00008c |
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 Biochemistry and Molecular Biophysics Blood and Lymphatics Parasitology 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 SDG 3 - Good Health and Well-being Transport and Circulation cancer Neoplasms (MeSH) neoplastic disease dermatological disorder integumentary system disease genome growth inhibition malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease metabolic network multi-drug resistance neurological disorder nervous system disease polypharmacology profile proteins drug target
