Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening

Elumalai Pavadai, Farah El Mazouni, Sergio Wittlin, Carmen De Kock, Margaret A. Phillips, Kelly Chibale

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent PfDHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known PfDHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of PfDHODH at a concentration of 10 μM, three of which exhibited IC50 values in the range of 0.38-20 μM. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC50 values of ≤50 μM, 4 of which showed IC50 values in the range of 5-12 μM. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors.

Original languageEnglish (US)
Pages (from-to)548-562
Number of pages15
JournalJournal of Chemical Information and Modeling
Volume56
Issue number3
DOIs
StatePublished - Mar 28 2016

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Screening
Values
mechanic
cancer
drug
energy
Growth Inhibitors
Molecular mechanics
Biosynthesis
Antimalarials
Binding energy
Parasites
dihydroorotate dehydrogenase
Oxidoreductases
Enzymes

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening. / Pavadai, Elumalai; El Mazouni, Farah; Wittlin, Sergio; De Kock, Carmen; Phillips, Margaret A.; Chibale, Kelly.

In: Journal of Chemical Information and Modeling, Vol. 56, No. 3, 28.03.2016, p. 548-562.

Research output: Contribution to journalArticle

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abstract = "Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent PfDHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known PfDHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25{\%} inhibition of PfDHODH at a concentration of 10 μM, three of which exhibited IC50 values in the range of 0.38-20 μM. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC50 values of ≤50 μM, 4 of which showed IC50 values in the range of 5-12 μM. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors.",
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