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- Publisher Website: 10.1039/c2mb00008c
- Scopus: eid_2-s2.0-84861142400
- PMID: 22446744
- WOS: WOS:000303776200008
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Article: Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads
Title | Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads |
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Authors | |
Issue Date | 2012 |
Publisher | Royal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/is/journals/current/mbs/mbspub.htm |
Citation | Molecular Biosystems, 2012, v. 8 n. 6, p. 1678-1685 How to Cite? |
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. © 2012 The Royal Society of Chemistry. |
Persistent Identifier | http://hdl.handle.net/10722/181266 |
ISSN | 2019 Impact Factor: 3.336 2020 SCImago Journal Rankings: 0.942 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Jensen, K | en_US |
dc.contributor.author | Plichta, D | en_US |
dc.contributor.author | Panagiotou, G | en_US |
dc.contributor.author | Kouskoumvekaki, I | en_US |
dc.date.accessioned | 2013-02-21T02:03:37Z | - |
dc.date.available | 2013-02-21T02:03:37Z | - |
dc.date.issued | 2012 | en_US |
dc.identifier.citation | Molecular Biosystems, 2012, v. 8 n. 6, p. 1678-1685 | en_US |
dc.identifier.issn | 1742-206X | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/181266 | - |
dc.description.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. © 2012 The Royal Society of Chemistry. | en_US |
dc.language | eng | en_US |
dc.publisher | Royal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/is/journals/current/mbs/mbspub.htm | en_US |
dc.relation.ispartof | Molecular BioSystems | en_US |
dc.subject.mesh | Antimalarials - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Chromosome Mapping | en_US |
dc.subject.mesh | Cluster Analysis | en_US |
dc.subject.mesh | Drug Discovery - Methods | en_US |
dc.subject.mesh | Genome, Protozoan | en_US |
dc.subject.mesh | Genomics - Methods | en_US |
dc.subject.mesh | Plasmodium Falciparum - Drug Effects - Genetics | en_US |
dc.subject.mesh | Small Molecule Libraries - Chemistry - Pharmacology | en_US |
dc.title | Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads | en_US |
dc.type | Article | en_US |
dc.identifier.email | Panagiotou, G: gipa@hku.hk | en_US |
dc.identifier.authority | Panagiotou, G=rp01725 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1039/c2mb00008c | en_US |
dc.identifier.pmid | 22446744 | - |
dc.identifier.scopus | eid_2-s2.0-84861142400 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-84861142400&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 8 | en_US |
dc.identifier.issue | 6 | en_US |
dc.identifier.spage | 1678 | en_US |
dc.identifier.epage | 1685 | en_US |
dc.identifier.isi | WOS:000303776200008 | - |
dc.publisher.place | United Kingdom | en_US |
dc.identifier.scopusauthorid | Jensen, K=7401675251 | en_US |
dc.identifier.scopusauthorid | Plichta, D=55220409000 | en_US |
dc.identifier.scopusauthorid | Panagiotou, G=8566179700 | en_US |
dc.identifier.scopusauthorid | Kouskoumvekaki, I=6602787035 | en_US |
dc.identifier.issnl | 1742-2051 | - |