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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 | ||||||
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 |
DHODH | Pf3D7_06_v3:130,191..132,792(-) | DHOD | PFF0160c |
Database Links | |
Alphafold | Q08210 (Pf3D7) |
ChEMBL Target | CHEMBL3588732 (Pf3D7) |
PlasmoDB | PF3D7_0603300 (Pf3D7) |
SynPHARM |
85411 (in complex with DSM421) 85410 (in complex with DSM421) 85405 (in complex with DSM421) |
UniProtKB | Q08210 (Pf3D7) |
Selected 3D Structures | |||||||||||||
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific inhibitor tables |
Whole Organism Assay Data Linked to This Target | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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]. |
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]
Nucleoside synthesis and metabolism (Plasmodium spp.): Plasmodium falciparum dihydroorotate dehydrogenase. Last modified on 20/10/2021. Accessed on 03/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2949.