Target Information

Target General Information

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Target ID

T61400 (Former ID: TTDI00862)

Target Name

Dihydroorotate dehydrogenase (DHODH)

Synonyms

Dihydroorotate oxidase; Dihydroorotate dehydrogenase (quinone), mitochondrial; DHOdehase; DHODH

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Gene Name

DHODH

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Hyper-lipoproteinaemia [ICD-11: 5C80]

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

UniProt ID

PYRD_HUMAN

EC Number

EC 1.3.5.2

Sequence

MAWRHLKKRAQDAVIILGGGGLLFASYLMATGDERFYAEHLMPTLQGLLDPESAHRLAVR
FTSLGLLPRARFQDSDMLEVRVLGHKFRNPVGIAAGFDKHGEAVDGLYKMGFGFVEIGSV
TPKPQEGNPRPRVFRLPEDQAVINRYGFNSHGLSVVEHRLRARQQKQAKLTEDGLPLGVN
LGKNKTSVDAAEDYAEGVRVLGPLADYLVVNVSSPNTAGLRSLQGKAELRRLLTKVLQER
DGLRRVHRPAVLVKIAPDLTSQDKEDIASVVKELGIDGLIVTNTTVSRPAGLQGALRSET
GGLSGKPLRDLSTQTIREMYALTQGRVPIIGVGGVSSGQDALEKIRAGASLVQLYTALTF
WGPPVVGKVKRELEALLKEQGFGGVTDAIGADHRR

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3D Structure

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PDB

HIT2.0 ID

T14V9R

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Teriflunomide

Drug Info

Approved

Hyperlipidaemia

[2]

Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

BREQUINAR

Drug Info

Phase 2

Coronavirus Disease 2019 (COVID-19)

[3]

Vidofludimus

Drug Info

Phase 2

Inflammatory bowel disease

[4]

BAY2402234

Drug Info

Phase 1

Myeloid leukaemia

[5]

LAS-186323

Drug Info

Phase 1

Multiple sclerosis

[6]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

FK778

Drug Info

Discontinued in Phase 2

Kidney/heart transplant rejection

[7]

HR325

Drug Info

Discontinued in Phase 2

Rheumatoid arthritis

[8]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 5 Modulator drugs

Teriflunomide

Drug Info

[1]

BREQUINAR

Drug Info

[9]

Vidofludimus

Drug Info

[10]

FK778

Drug Info

[12]

HR325

Drug Info

[13]

Inhibitor

[+] 2 Inhibitor drugs

BAY2402234

Drug Info

[5]

LAS-186323

Drug Info

[11]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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

[14]

PDB Sequence

MATGDERFYA

³⁹

EHLMPTLQGL

⁴⁹

LDPESAHRLA

⁵⁹

VRFTSLGLLP

⁶⁹

FQDSDMLEVR

⁸²

VLGHKFRNPV

⁹²

GIAAGFDKHG

¹⁰²

EAVDGLYKMG

¹¹²

FGFVEIGSVT

¹²²

PKPQEGNPRP

¹³²

RVFRLPEDQA

¹⁴²

VINRYGFNSH

¹⁵²

GLSVVEHRLR

¹⁶²

ARQQKQAKLT

¹⁷²

EDGLPLGVNL

¹⁸²

GKNKTSVDAA

¹⁹²

EDYAEGVRVL

²⁰²

GPLADYLVVN

²¹²

VSSPNTAGLR

²²²

SLQGKAELRR

²³²

LLTKVLQERD

²⁴²

GLRRVHRPAV

²⁵²

LVKIAPDLTS

²⁶²

QDKEDIASVV

²⁷²

KELGIDGLIV

²⁸²

TNTTVSRPAG

²⁹²

LQGALRSETG

³⁰²

GLSGKPLRDL

³¹²

STQTIREMYA

³²²

LTQGRVPIIG

³³²

VGGVSSGQDA

³⁴²

LEKIRAGASL

³⁵²

VQLYTALTFW

³⁶²

GPPVVGKVKR

³⁷²

ELEALLKEQG

³⁸²

FGGVTDAIGA

³⁹²

DHRR

Residue

Distance (Å)

MET43

3.668

LEU46

4.709

GLN47

4.764

PRO52

3.314

ALA55

3.759

HIS56

3.342

ALA59

3.536

THR63

4.110

PHE98

3.366

MET111

3.959

Residue

Distance (Å)

VAL134

3.883

ARG136

3.167

VAL143

4.897

TYR147

4.933

TYR356

2.810

LEU359

3.291

THR360

3.419

GLY363

3.685

PRO364

3.295

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

[15]

PDB Sequence

TGDERFYAEH

⁴¹

LMPTLQGLLD

⁵¹

PESAHRLAVR

⁶¹

FTSLGLLPRA

⁷¹

RFQDSDMLEV

⁸¹

RVLGHKFRNP

⁹¹

VGIAAGFDKH

¹⁰¹

GEAVDGLYKM

¹¹¹

GFGFVEIGSV

¹²¹

TPKPQEGNPR

¹³¹

PRVFRLPEDQ

¹⁴¹

AVINRYGFNS

¹⁵¹

HGLSVVEHRL

¹⁶¹

RARQQKQAKL

¹⁷¹

TEDGLPLGVN

¹⁸¹

LGKNKTSVDA

¹⁹¹

AEDYAEGVRV

²⁰¹

LGPLADYLVV

²¹¹

NVSSPNTAGL

²²¹

RSLQGKAELR

²³¹

RLLTKVLQER

²⁴¹

DGLRRVHRPA

²⁵¹

VLVKIAPDLT

²⁶¹

SQDKEDIASV

²⁷¹

VKELGIDGLI

²⁸¹

VTNTTVSRPA

²⁹¹

GLQGALRSET

³⁰¹

GGLSGKPLRD

³¹¹

LSTQTIREMY

³²¹

ALTQGRVPII

³³¹

GVGGVSSGQD

³⁴¹

ALEKIRAGAS

³⁵¹

LVQLYTATFW

³⁶²

GPPVVGKVKR

³⁷²

ELEALLKEQG

³⁸²

FGGVTDAIGA

³⁹²

DHRR

Residue

Distance (Å)

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

Residue

Distance (Å)

PHE98

3.758

MET111

4.296

VAL134

3.577

ARG136

4.022

VAL143

3.947

TYR147

4.863

TYR356

2.747

THR360

3.403

GLY363

4.155

PRO364

3.319

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

Top

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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Pyrimidine metabolism	hsa00240	Affiliated Target
Class: Metabolism => Nucleotide metabolism	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	0.00E+00
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

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Pyrimidine metabolism

Metabolic pathways

Panther Pathway

[+] 1 Panther Pathways

De novo pyrimidine ribonucleotides biosythesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Pyrimidine Metabolism

Reactome

[+] 1 Reactome Pathways

Pyrimidine biosynthesis

WikiPathways

[+] 1 WikiPathways

Metabolism of nucleotides

References

Top

REF 1

Nat Rev Drug Discov. 2013 Feb;12(2):87-90.

REF 2

Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.

REF 3

ClinicalTrials.gov (NCT04575038) CRISIS2: A Phase 2 Study of the Safety and Antiviral Activity of Brequinar in Non-hospitalized Pts With COVID-19 (CRISIS2). U.S. National Institutes of Health.

REF 4

2011 Pipeline of 4SC AG.

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028859)

REF 7

New developments in immunosuppressive therapy for heart transplantation. Expert Opin Emerg Drugs. 2009 Mar;14(1):1-21.

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005016)

REF 9

DOI: 10.1203/00006450-198807000-00137

REF 10

Company report (4SC)

REF 11

Clinical pipeline report, company report or official report of Aslanpharma.

REF 12

Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model. Transplantation. 2003 Dec 15;76(11):1627-9.

REF 13

In vitro and in Vivo inhibition of immunoglobulin secretion by the immunosuppressive compound HR325 is reversed by exogenous uridine. Scand J Immunol. 2002 Jul;56(1):35-42.

REF 14

Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure. 2000 Jan 15;8(1):25-33.

REF 15

Crystal structure of human dihydroorotate dehydrogenase (DHODH) with Piperine

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