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

Cite this

Jensen, Kasper ; Plichta, Damian Rafal ; Panagiotou, Gianni ; Kouskoumvekaki, Irene. / Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads. In: Molecular BioSystems. 2012 ; Vol. 8, No. 6. pp. 1678-1685.
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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.",
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author = "Kasper Jensen and Plichta, {Damian Rafal} and Gianni Panagiotou and Irene Kouskoumvekaki",
year = "2012",
doi = "10.1039/c2mb00008c",
language = "English",
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pages = "1678--1685",
journal = "Molecular BioSystems",
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Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads. / Jensen, Kasper; Plichta, Damian Rafal; Panagiotou, Gianni; Kouskoumvekaki, Irene.

In: Molecular BioSystems, Vol. 8, No. 6, 2012, p. 1678-1685.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads

AU - Jensen, Kasper

AU - Plichta, Damian Rafal

AU - Panagiotou, Gianni

AU - Kouskoumvekaki, Irene

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - genome

KW - growth inhibition

KW - metabolic network

KW - multi-drug resistance

KW - polypharmacology profile

KW - cancer Neoplasms (MeSH) neoplastic disease

KW - dermatological disorder integumentary system disease

KW - malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease

KW - neurological disorder nervous system disease

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common host

KW - Protozoa Invertebrata Animalia (Animals, Invertebrates, Microorganisms, Protozoans) - Sporozoa [35400] Plasmodium falciparum species parasite strain-D2d

KW - proteins drug target

KW - 10060, Biochemistry studies - General

KW - 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines

KW - 10064, Biochemistry studies - Proteins, peptides and amino acids

KW - 15002, Blood - Blood and lymph studies

KW - 15004, Blood - Blood cell studies

KW - 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies

KW - 18506, Integumentary system - Pathology

KW - 20506, Nervous system - Pathology

KW - 24004, Neoplasms - Pathology, clinical aspects and systemic effects

KW - 60502, Parasitology - General

KW - 60504, Parasitology - Medical

KW - 64002, Invertebrata: comparative, experimental morphology, physiology and pathology - Protozoa

KW - Transport and Circulation

KW - Biochemistry and Molecular Biophysics

KW - Blood and Lymphatics

KW - Parasitology

U2 - 10.1039/c2mb00008c

DO - 10.1039/c2mb00008c

M3 - Journal article

VL - 8

SP - 1678

EP - 1685

JO - Molecular BioSystems

JF - Molecular BioSystems

SN - 1742-206X

IS - 6

ER -