Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads
| Autor: | Irene Kouskoumvekaki, Damian R. Plichta, Kasper P. Jensen, Gianni Panagiotou |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
60504
Parasitology - Medical Druggability 10060 Biochemistry studies - General Drug resistance Protozoa Invertebrata Animalia (Animals Invertebrates Microorganisms Protozoans) - Sporozoa [35400] Plasmodium falciparum species parasite strain-D2d Chemical library growth inhibition comparative experimental morphology physiology and pathology - Protozoa [64002 Invertebrata] chemistry.chemical_compound Drug Discovery Cluster Analysis 15002 Blood - Blood and lymph studies polypharmacology profile cancer Neoplasms (MeSH) neoplastic disease Chromosome Mapping Genomics 15006 Blood - Blood lymphatic and reticuloendothelial pathologies 60502 Parasitology - General 15004 Blood - Blood cell studies Proteome multi-drug resistance Biotechnology neurological disorder nervous system disease Plasmodium falciparum Computational biology Biology Small Molecule Libraries proteins drug target Antimalarials SDG 3 - Good Health and Well-being Transport and Circulation metabolic network parasitic diseases medicine 10062 Biochemistry studies - Nucleic acids purines and pyrimidines genome Molecular Biology 18506 Integumentary system - Pathology 10064 Biochemistry studies - Proteins peptides and amino acids Biochemistry and Molecular Biophysics dermatological disorder integumentary system disease medicine.disease biology.organism_classification 24004 Neoplasms - Pathology clinical aspects and systemic effects Chemical space 20506 Nervous system - Pathology Parasitology chemistry Primates Mammalia Vertebrata Chordata Animalia (Animals Chordates Humans Mammals Primates Vertebrates) - Hominidae [86215] human common host Immunology malaria Malaria (MeSH) blood and lymphatic disease parasitic disease Blood and Lymphatics Genome Protozoan Malaria |
| Zdroj: | Jensen, K, Plichta, D R, Panagiotou, G & Kouskoumvekaki, I 2012, ' Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads ', Molecular BioSystems, vol. 8, no. 6, pp. 1678-1685 . https://doi.org/10.1039/c2mb00008c |
| ISSN: | 1742-2051 |
| DOI: | 10.1039/c2mb00008c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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