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Plasmodium falciparum dihydroorotate dehydrogenase

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Target not currently curated in GtoImmuPdb

Malaria Pharmacology Ligand  Target has curated data in GtoMPdb

Target id: 2949

Nomenclature: Plasmodium falciparum dihydroorotate dehydrogenase

Abbreviated Name: PfDHODH

Family: Nucleoside synthesis and metabolism (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 569 DHODH dihydroorotate dehydrogenase
Previous and Unofficial Names Click here for help
Pfal DHODH
Database Links Click here for help
ChEMBL Target
PlasmoDB
SynPHARM
UniProtKB
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421
PDB Id:  5TBO
Ligand:  DSM421
Resolution:  2.151Å
Species:  Plasmodium falciparum
References:  5

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BRD9185 Small molecule or natural product Pf Inhibition 7.9 pIC50 2
pIC50 7.9 (IC50 1.2x10-8 M) [2]
DSM502 Small molecule or natural product Pv Inhibition 7.8 pIC50 1
pIC50 7.8 (IC50 1.4x10-8 M) [1]
Description: Steady-state kinetic analysis.
DSM502 Small molecule or natural product Pf Inhibition 7.7 pIC50 1
pIC50 7.7 (IC50 2x10-8 M) [1]
Description: Steady-state kinetic analysis.
DSM265 Small molecule or natural product Ligand has a PDB structure Pf Inhibition 7.5 pIC50 1
pIC50 7.5 (IC50 3x10-8 M) [1]
Description: Steady-state kinetic analysis.
DSM421 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Pf Inhibition 7.3 pIC50 5
pIC50 7.3 (IC50 5.3x10-8 M) [5]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM265 Small molecule or natural product Ligand has a PDB structure Pv Inhibition 7.1 pIC50 1
pIC50 7.1 (IC50 7.2x10-8 M) [1]
Description: Steady-state kinetic analysis.
DSM421 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Pv Inhibition 7.0 pIC50 5
pIC50 7.0 (IC50 9.4x10-8 M) [5]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
View species-specific inhibitor tables
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
DSM502 Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 7.8 pEC50 1
pEC50 7.8 (EC50 1.4x10-8 M) SYBR Green I [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM502 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 7.8 pEC50 1
pEC50 7.8 (EC50 1.6x10-8 M) SYBR Green I [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
BRD9185 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 7.8 pEC50 2
pEC50 7.8 (EC50 1.6x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Small molecule or natural product Ligand has a PDB structure Pf3D7 Parasite growth inhibition assay - - 7.4 – 7.8 pEC50 5
pEC50 7.8 (EC50 1.4x10-8 M) SYBR Green incorporation (72h assay) [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pEC50 7.4 (EC50 4.3x10-8 M) SYBR Green incorporation (48h assay) [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Small molecule or natural product Ligand has a PDB structure Pv Blood-stage: schizont maturation assay using P. vivax field isolates. - - 6.7 pEC50 5
pEC50 6.7 (EC50 1.8x10-7 M) [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM265 Small molecule or natural product Ligand has a PDB structure PfNF54 Parasite growth inhibition assay - - 7.5 pIC50 3
pIC50 7.5 (IC50 3x10-8 M) [3H]-hypoxanthine incorporation [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Malaria Pharmacology Comments
The pyrimidine biosynthetic pathway has facilitated the successful identification of antimalarial drug targets. These include the fourth enzyme in the pathway as P. falciparum dihydroorotate dehydrogenase (PfDHODH) [4]. In this publication they established that the cross reactivity with human DHODH was orders of magnitude lower.

References

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1. Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J et al.. (2020) Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria. J Med Chem, 63 (9): 4929-4956. [PMID:32248693]

2. Maetani M, Kato N, Jabor VAP, Calil FA, Nonato MC, Scherer CA, Schreiber SL. (2017) Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparum Dihydroorotate Dehydrogenase. ACS Med Chem Lett, 8 (4): 438-442. [PMID:28435533]

3. Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, Njoroge JW, El Mazouni F, Lao Y, Kokkonda S et al.. (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med, 7 (296): 296ra111. [PMID:26180101]

4. Phillips MA, Rathod PK. (2010) Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets, 10 (3): 226-39. [PMID:20334617]

5. Phillips MA, White KL, Kokkonda S, Deng X, White J, El Mazouni F, Marsh K, Tomchick DR, Manjalanagara K, Rudra KR et al.. (2016) A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. ACS Infect Dis, 2 (12): 945-957. [PMID:27641613]

How to cite this page

Nucleoside synthesis and metabolism (Plasmodium spp.): Plasmodium falciparum dihydroorotate dehydrogenase. Last modified on 16/03/2021. Accessed on 14/06/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2949.