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Plasmodium falciparum dihydroorotate dehydrogenase

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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
Gene and Protein Information Comments
Our dihydroorotate dehydrogenase (quinone) summary page provides information about the homologous human target.
Previous and Unofficial Names Click here for help
DHOD | PFF0160c
Database Links Click here for help
Alphafold
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 3D7
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM705
PDB Id:  7KZ4
Ligand:  DSM705
Resolution:  1.75Å
Species:  Plasmodium falciparum 3D7
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM265
PDB Id:  4RX0
Ligand:  DSM265
Resolution:  2.25Å
Species:  Plasmodium falciparum 3D7
References:  7

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 Guide to Malaria Pharmacology Ligand Pf Inhibition 7.9 pIC50 5
pIC50 7.9 (IC50 1.2x10-8 M) [5]
DSM502 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pv Inhibition 7.8 pIC50 3
pIC50 7.8 (IC50 1.4x10-8 M) [3]
Description: Steady-state kinetic analysis.
DSM502 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf Inhibition 7.7 pIC50 3
pIC50 7.7 (IC50 2x10-8 M) [3]
Description: Steady-state kinetic analysis.
DSM265 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf Inhibition 7.5 pIC50 3
pIC50 7.5 (IC50 3x10-8 M) [3]
Description: Steady-state kinetic analysis.
DSM421 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf Inhibition 7.3 pIC50 9
pIC50 7.3 (IC50 5.3x10-8 M) [9]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM705 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pv Inhibition 7.3 pIC50 6
pIC50 7.3 (IC50 5.2x10-8 M) [6]
Description: Steady-state kinetic analysis.
DSM265 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pv Inhibition 7.1 pIC50 3
pIC50 7.1 (IC50 7.2x10-8 M) [3]
Description: Steady-state kinetic analysis.
DSM421 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pv Inhibition 7.0 pIC50 9
pIC50 7.0 (IC50 9.4x10-8 M) [9]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM705 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf Inhibition 7.0 pIC50 6
pIC50 7.0 (IC50 9.5x10-8 M) [6]
Description: Steady-state kinetic analysis.
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
DSM705 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.9 pEC50 6
pEC50 7.9 (EC50 1.2x10-8 M) SYBR Green I assay (72h) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM705 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pb Parasite liver stage assay - - 7.9 pEC50 6
pEC50 7.9 (EC50 1.3x10-8 M) Luciferase bioluminescence (Pbluc) assay to measure sporozoite invasion into HepG2 liver cells (prophylactic activity) [6]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
DSM502 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.8 pEC50 3
pEC50 7.8 (EC50 1.4x10-8 M) SYBR Green I [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM502 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 7.8 pEC50 3
pEC50 7.8 (EC50 1.6x10-8 M) SYBR Green I [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
BRD9185 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 7.8 pEC50 5
pEC50 7.8 (EC50 1.6x10-8 M) SYBR Green I assay [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.4 – 7.8 pEC50 9
pEC50 7.8 (EC50 1.4x10-8 M) SYBR Green incorporation (72h assay) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pEC50 7.4 (EC50 4.3x10-8 M) SYBR Green incorporation (48h assay) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pv Blood-stage: schizont maturation assay using P. vivax field isolates. - - 6.7 pEC50 9
pEC50 6.7 (EC50 1.8x10-7 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM265 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfNF54 Parasite growth inhibition assay - - 7.5 pIC50 7
pIC50 7.5 (IC50 3x10-8 M) [3H]-hypoxanthine incorporation [7]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Malaria Pharmacology Comments
P. falciparum dihydroorotate dehydrogenase (PfDHODH) is the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway [4]. In contrast to its human host, the malaria parasite lacks pyrimidine salvage enzymes and the de novo pathway is an essential source of pyrimidines for cell growth and has facilitated the validation of PfDHODH as a potential target for antimalarial therapy [8].
A number of chemical series have been identified that are potent and selective inhibitors of PfDHODH, these include: the triazolopyrimidines [2], thiophene-2-carboxamides [1], azetidine-2-carbonitriles [5] and more recently a pyrrole-based series [6].

References

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1. Booker ML, Bastos CM, Kramer ML, Barker Jr RH, Skerlj R, Sidhu AB, Deng X, Celatka C, Cortese JF, Guerrero Bravo JE et al.. (2010) Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem, 285 (43): 33054-33064. [PMID:20702404]

2. Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, Koltun M, El Mazouni F, Kokkonda S, Katneni K et al.. (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem, 54 (15): 5540-61. [PMID:21696174]

3. 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]

4. LeBlanc SB, Wilson CM. (1993) The dihydroorotate dehydrogenase gene homologue of Plasmodium falciparum. Mol Biochem Parasitol, 60 (2): 349-51. [PMID:8232427]

5. 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]

6. Palmer MJ, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White KL, Striepen J et al.. (2021) Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series. J Med Chem, 64 (9): 6085-6136. [PMID:33876936]

7. 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]

8. 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]

9. 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 20/10/2021. Accessed on 17/08/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2949.