Target Information
Target General Information | Top | |||||
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Target ID |
T99009
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Target Name |
HUMAN dihydroorotate dehydrogenase (DHODH)
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Synonyms |
Dihydroorotate oxidase; Dihydroorotate dehydrogenase (quinone), mitochondrial; DHOdehase; DHODH
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Gene Name |
DHODH
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Disease | [+] 1 Target-related Diseases | + | ||||
1 | Multiple sclerosis [ICD-11: 8A40] | |||||
Function |
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
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BioChemical Class |
CH-CH donor oxidoreductase
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UniProt ID | ||||||
EC Number |
EC 1.3.5.2
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Sequence |
MAWRHLKKRAQDAVIILGGGGLLFASYLMATGDERFYAEHLMPTLQGLLDPESAHRLAVR
FTSLGLLPRARFQDSDMLEVRVLGHKFRNPVGIAAGFDKHGEAVDGLYKMGFGFVEIGSV TPKPQEGNPRPRVFRLPEDQAVINRYGFNSHGLSVVEHRLRARQQKQAKLTEDGLPLGVN LGKNKTSVDAAEDYAEGVRVLGPLADYLVVNVSSPNTAGLRSLQGKAELRRLLTKVLQER DGLRRVHRPAVLVKIAPDLTSQDKEDIASVVKELGIDGLIVTNTTVSRPAGLQGALRSET GGLSGKPLRDLSTQTIREMYALTQGRVPIIGVGGVSSGQDALEKIRAGASLVQLYTALTF WGPPVVGKVKRELEALLKEQGFGGVTDAIGADHRR Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
Drugs and Modes of Action | Top | |||||
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Drugs in Phase 1 Trial | [+] 1 | + | ||||
1 | Leflunomide | Drug Info | Approved | Multiple sclerosis | [2] | |
Drugs in Phase 2 Trial | [+] 1 | + | ||||
1 | IMU-838 | Drug Info | Phase 2/3 | Coronavirus Disease 2019 (COVID-19) | [3] | |
Preclinical Drugs | [+] 1 | + | ||||
1 | FA-613 | Drug Info | Preclinical | Severe acute respiratory syndrome (SARS) | [1] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | IMU-838 | Drug Info | [4] | |||
2 | Leflunomide | Drug Info | [4], [5] | |||
3 | FA-613 | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: Teriflunomide | Ligand Info | |||||
Structure Description | HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726 | PDB:1D3H | ||||
Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [6] |
PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 FQDSDMLEVR82 VLGHKFRNPV 92 GIAAGFDKHG102 EAVDGLYKMG112 FGFVEIGSVT122 PKPQEGNPRP132 RVFRLPEDQA 142 VINRYGFNSH152 GLSVVEHRLR162 ARQQKQAKLT172 EDGLPLGVNL182 GKNKTSVDAA 192 EDYAEGVRVL202 GPLADYLVVN212 VSSPNTAGLR222 SLQGKAELRR232 LLTKVLQERD 242 GLRRVHRPAV252 LVKIAPDLTS262 QDKEDIASVV272 KELGIDGLIV282 TNTTVSRPAG 292 LQGALRSETG302 GLSGKPLRDL312 STQTIREMYA322 LTQGRVPIIG332 VGGVSSGQDA 342 LEKIRAGASL352 VQLYTALTFW362 GPPVVGKVKR372 ELEALLKEQG382 FGGVTDAIGA 392 DHRR
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Ligand Name: Piperine | Ligand Info | |||||
Structure Description | Crystal structure of human dihydroorotate dehydrogenase (DHODH) with Piperine | PDB:6LZL | ||||
Method | X-ray diffraction | Resolution | 1.98 Å | Mutation | No | [7] |
PDB Sequence |
TGDERFYAEH
41 LMPTLQGLLD51 PESAHRLAVR61 FTSLGLLPRA71 RFQDSDMLEV81 RVLGHKFRNP 91 VGIAAGFDKH101 GEAVDGLYKM111 GFGFVEIGSV121 TPKPQEGNPR131 PRVFRLPEDQ 141 AVINRYGFNS151 HGLSVVEHRL161 RARQQKQAKL171 TEDGLPLGVN181 LGKNKTSVDA 191 AEDYAEGVRV201 LGPLADYLVV211 NVSSPNTAGL221 RSLQGKAELR231 RLLTKVLQER 241 DGLRRVHRPA251 VLVKIAPDLT261 SQDKEDIASV271 VKELGIDGLI281 VTNTTVSRPA 291 GLQGALRSET301 GGLSGKPLRD311 LSTQTIREMY321 ALTQGRVPII331 GVGGVSSGQD 341 ALEKIRAGAS351 LVQLYTATFW362 GPPVVGKVKR372 ELEALLKEQG382 FGGVTDAIGA 392 DHRR
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TYR38
3.463
LEU42
4.742
MET43
3.493
GLN47
4.418
PRO52
3.478
ALA55
4.152
HIS56
3.398
ALA59
3.295
PHE62
4.698
THR63
3.914
LEU68
3.832
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Pyrimidine metabolism | hsa00240 | Affiliated Target |
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Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy |
Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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Closeness centrality | 1.52E-01 | Radiality | 1.21E+01 | Clustering coefficient | 1.00E+00 |
Neighborhood connectivity | 1.15E+01 | Topological coefficient | 5.48E-01 | Eccentricity | 14 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
References | Top | |||||
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REF 1 | Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. J Gen Virol. 2017 May;98(5):946-954. | |||||
REF 2 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 077090. | |||||
REF 3 | ClinicalTrials.gov (NCT04379271) A Study to Evaluate the Efficacy, Safety and Tolerability of IMU-838 as Addition to Investigator's Choice of Standard of Care Therapy, in Patients With Coronavirus Disease 19 (COVID-19). U.S. National Institutes of Health. | |||||
REF 4 | IMU-838 Targeting DHODH | |||||
REF 5 | On dihydroorotate dehydrogenases and their inhibitors and uses. J Med Chem. 2013 Apr 25;56(8):3148-67. doi: 10.1021/jm301848w. | |||||
REF 6 | Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure. 2000 Jan 15;8(1):25-33. | |||||
REF 7 | Crystal structure of human dihydroorotate dehydrogenase (DHODH) with Piperine |
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