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dihydroorotate dehydrogenase (quinone)

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2604

Nomenclature: dihydroorotate dehydrogenase (quinone)

Abbreviated Name: DHODH

Family: Nucleoside synthesis and metabolism, 1.-.-.- Oxidoreductases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 395 16q22.2 DHODH dihydroorotate dehydrogenase (quinone)
Mouse 1 395 8 D3 Dhodh dihydroorotate dehydrogenase
Rat 1 395 19q12 Dhodh dihydroorotate dehydrogenase (quinone)
Gene and Protein Information Comments
The Antimalarial targets family provides information about P. falciparum DHODH.
Database Links Click here for help
Alphafold Q02127 (Hs), O35435 (Mm), Q63707 (Rn)
BRENDA 1.3.5.2
CATH/Gene3D 3.20.20.70
ChEMBL Target CHEMBL1966 (Hs), CHEMBL2991 (Mm), CHEMBL2383 (Rn)
DrugBank Target Q02127 (Hs)
Ensembl Gene ENSG00000102967 (Hs), ENSMUSG00000031730 (Mm), ENSRNOG00000015063 (Rn)
Entrez Gene 1723 (Hs), 56749 (Mm), 65156 (Rn)
Human Protein Atlas ENSG00000102967 (Hs)
KEGG Enzyme 1.3.5.2
KEGG Gene hsa:1723 (Hs), mmu:56749 (Mm), rno:65156 (Rn)
OMIM 126064 (Hs)
Orphanet ORPHA225386 (Hs)
Pharos Q02127 (Hs)
RefSeq Nucleotide NM_001361 (Hs), NM_020046 (Mm), NM_001008553 (Rn)
RefSeq Protein NP_001352 (Hs), NP_064430 (Mm), NP_001008553 (Rn)
SynPHARM 78875 (in complex with teriflunomide)
UniProtKB Q02127 (Hs), O35435 (Mm), Q63707 (Rn)
Wikipedia DHODH (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human DHODH in complex with BAY 2402234
PDB Id:  6QU7
Ligand:  orludodstat
Resolution:  1.52Å
Species:  Human
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog
PDB Id:  4IGH
Resolution:  1.3Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 1.3.5.2

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
S416 Small molecule or natural product Ligand has a PDB structure Hs Binding 8.8 pKd 15
⤷ pKd 8.8 (Kd 1.69x10-9 M) [15]
compound 19 [PMID: 35925768] Small molecule or natural product Ligand has a PDB structure Hs Binding 8.5 pKd 3
⤷ pKd 8.5 (Kd 3.3x10-9 M) [3]
Description: Binding affinity determined by SPR
S312 Small molecule or natural product Ligand has a PDB structure Hs Binding 7.7 pKd 15
⤷ pKd 7.7 (Kd 2.03x10-8 M) [15]
teriflunomide Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pKi 5
⤷ pKi 7.5 (Ki 3x10-8 M) [5]
brequinar Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.0 pKi 12
⤷ pKi 7.0 (Ki 1x10-7 M) [12]
leflunomide Small molecule or natural product Approved drug Primary target of this compound Immunopharmacology Ligand Hs Inhibition 4.9 pKi 11
⤷ pKi 4.9 (Ki 1.3x10-5 M) [11]
compound 19 [PMID: 35925768] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.0 pIC50 3
⤷ pIC50 9.0 (IC50 1.1x10-9 M) [3]
Description: Inhibition of hDHODH enzymatic activity in vitro
orludodstat Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.9 pIC50 2
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [2]
compound 19 [PMID: 35925768] Small molecule or natural product Ligand has a PDB structure Monkey Inhibition 8.8 pIC50 3
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [3]
S416 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.1 pIC50 15
⤷ pIC50 8.1 (IC50 7.5x10-9 M) [15]
S312 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.5 pIC50 15
⤷ pIC50 7.5 (IC50 2.92x10-8 M) [15]
farudodstat Small molecule or natural product Hs Inhibition 7.5 pIC50 16
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [16]
vidofludimus Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 6
⤷ pIC50 7.3 (IC50 4.8x10-8 M) [6]
Description: Determined in an indirect in vitro enzyme assay which measures the reduced co-substrate ubiquinone.
compound 19 [PMID: 35925768] Small molecule or natural product Ligand has a PDB structure Mm Inhibition 6.8 pIC50 3
⤷ pIC50 6.8 (IC50 1.4x10-7 M) [3]
teriflunomide Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 15
⤷ pIC50 6.5 (IC50 3.071x10-7 M) [15]
vidofludimus Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Rn Inhibition 6.3 pIC50 6
⤷ pIC50 6.3 (IC50 4.6x10-7 M) [6]
compound 19 [PMID: 35925768] Small molecule or natural product Ligand has a PDB structure Rn Inhibition 5.8 pIC50 3
⤷ pIC50 5.8 (IC50 1.58x10-6 M) [3]
vidofludimus Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Mm Inhibition 5.4 pIC50 6
⤷ pIC50 5.4 (IC50 3.8x10-6 M) [6]
BRD9185 Small molecule or natural product Guide to Malaria Pharmacology Ligand Hs Inhibition <4.3 pIC50 7
⤷ pIC50 <4.3 (IC50 >5x10-5 M) [7]
DSM421 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Inhibition <4.0 pIC50 13
⤷ pIC50 <4.0 (IC50 >1x10-4 M) [13]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
DSM421 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Mm Inhibition <4.0 pIC50 13
⤷ pIC50 <4.0 (IC50 >1x10-4 M) [13]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
DSM421 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Rn Inhibition <4.0 pIC50 13
⤷ pIC50 <4.0 (IC50 >1x10-4 M) [13]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
DSM705 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Inhibition <4.0 pIC50 10
⤷ pIC50 <4.0 (IC50 >1x10-4 M) [10]
Description: Steady-state kinetic analysis.
emvododstat Small molecule or natural product Hs Inhibition - - 1
⤷ [1]
View species-specific inhibitor tables
Immunopharmacology Comments
Dihydroorotate dehydrogenase (DHODH) is the fourth, and rate-limiting enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway, but the enzyme's expression is selectively upregulated in proliferating and activated lymphocytes, making it a target susceptible to pharmacological inhibition in activated immune cells. Inhibition of DHODH causes a reduction in the available pyrimidine pool, which leads to metabolic stress and apoptosis in highly activated cells.

DHODH inhibitors are used clinically to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide respectively) [9]. Vidofludimus was a Phase 2 clinical candidate for IBD and RA, but has been superceded by IMU-838 which is an orally active polymorph of vidofludimus calcium (PubChem CID: 56944639) that is under evaluation for clinical efficacy in ulcerative colitis (NCT03341962), primary sclerosing cholangitis (NCT03722576) and multiple sclerosis (NCT03846219) [8].
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Postaxial acrofacial dysostosis
Synonyms: Miller syndrome
OMIM: 263750
Orphanet: ORPHA246
General Comments
Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. DHODH inhibitors are used clinically to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide respectively) and have been investigated in oncology, virology, and parasitology (e.g. malaria) [9]. More information about P. falciparum DHODH (gene symbol PF3D7_0603300 for P. falciparum strain 3D7) as an antimalarial drug target is contained in our evolving Antimalarial targets family.

DHODH has also been proposed as a host enzyme whose inhibition could have antiviral effects [15], based on evidence which confirms that viruses are highly dependent on host pyrimidine synthesis for the supply of RNA precursors that they rely on for replication. Several DHODH inhibitors have reported anti-SARS-CoV-2 activity [14], and the combination of these with drugs that inhibit the viral RNA-dependent RNA polymerase (e.g. molnupiravir and remdesivir) have demonstrated synergistic/additive antiviral activity in mice [14]. PTC Therapeutics are taking their DHODH inhibitor PTC299 forward in hospitalised COVID-19 patients (phase 2/3 NCT04439071).

References

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1. Cao L, Weetall M, Trotta C, Cintron K, Ma J, Kim MJ, Furia B, Romfo C, Graci JD, Li W et al.. (2019) Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties. Mol Cancer Ther, 18 (1): 3-16. [PMID:30352802]

2. Christian S, Merz C, Evans L, Gradl S, Seidel H, Friberg A, Eheim A, Lejeune P, Brzezinka K, Zimmermann K et al.. (2019) The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia, 33 (10): 2403-2415. [PMID:30940908]

3. Cisar JS, Pietsch C, DeRatt LG, Jacoby E, Kazmi F, Keohane C, Legenski K, Matico R, Shaffer P, Simonnet Y et al.. (2022) N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia. J Med Chem, 65 (16): 11241-11256. [PMID:35925768]

4. Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK. (2013) SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity. ACS Med Chem Lett, 4 (6): 517-521. [PMID:23930152]

5. Heikkilä T, Ramsey C, Davies M, Galtier C, Stead AM, Johnson AP, Fishwick CW, Boa AN, McConkey GA. (2007) Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J Med Chem, 50 (2): 186-91. [PMID:17228860]

6. Kulkarni OP, Sayyed SG, Kantner C, Ryu M, Schnurr M, Sárdy M, Leban J, Jankowsky R, Ammendola A, Doblhofer R et al.. (2010) 4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice. Am J Pathol, 176 (6): 2840-7. [PMID:20413687]

7. 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]

8. Muehler A, Peelen E, Kohlhof H, Gröppel M, Vitt D. (2020) Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord, 43: 102129. [PMID:32428844]

9. Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL. (2013) On dihydroorotate dehydrogenases and their inhibitors and uses. J Med Chem, 56 (8): 3148-67. [PMID:23452331]

10. 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]

11. Papageorgiou C, Albert R, Floersheim P, Lemaire M, Bitch F, Weber HP, Andersen E, Hungerford V, Schreier MH. (1998) Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations. J Med Chem, 41 (18): 3530-8. [PMID:9719606]

12. Peters GJ, Sharma SL, Laurensse E, Pinedo HM. (1987) Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). Invest New Drugs, 5 (3): 235-44. [PMID:2822596]

13. 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]

14. Schultz DC, Johnson RM, Ayyanathan K, Miller J, Whig K, Kamalia B, Dittmar M, Weston S, Hammond HL, Dillen C et al.. (2022) Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2. Nature, 604 (7904): 134-140. [PMID:35130559]

15. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang Y, Zhao Y, Wu Y, Shang W, Jiang X et al.. (2020) Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell, 11 (10): 723-739. [PMID:32754890]

16. Zhou J, Yiying Quah J, Ng Y, Chooi JY, Hui-Min Toh S, Lin B, Zea Tan T, Hosoi H, Osato M, Seet Q et al.. (2020) ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia. Haematologica, 105 (9): 2286-2297. [PMID:33054053]

How to cite this page

Nucleoside synthesis and metabolism: dihydroorotate dehydrogenase (quinone). Last modified on 05/08/2022. Accessed on 09/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2604.