Target Information

Target General Information

Target ID

T01318 (Former ID: TTDS00059)

Target Name

Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase)

Synonyms

PFF0160c; Mitochondrially bound dihydroorotate-ubiqui oxidoreductase; Dihydroorotate oxidase of Plasmodium falciparum; Dihydroorotate dehydrogenase of Plasmodium falciparum; DHOdehase of Plasmodium falciparum; DHODase; DHODH of Plasmodium falciparum; DHOD

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Gene Name

Malaria DHOdehase

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

Fungal infection [ICD-11: 1F29-1F2F]

Hyper-lipoproteinaemia [ICD-11: 5C80]

Malaria [ICD-11: 1F40-1F45]

Multiple sclerosis [ICD-11: 8A40]

Rheumatoid arthritis [ICD-11: FA20]

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_PLAF7

EC Number

EC 1.3.5.2

Sequence

MISKLKPQFMFLPKKHILSYCRKDVLNLFEQKFYYTSKRKESNNMKNESLLRLINYNRYY
NKIDSNNYYNGGKILSNDRQYIYSPLCEYKKKINDISSYVSVPFKINIRNLGTSNFVNNK
KDVLDNDYIYENIKKEKSKHKKIIFLLFVSLFGLYGFFESYNPEFFLYDIFLKFCLKYID
GEICHDLFLLLGKYNILPYDTSNDSIYACTNIKHLDFINPFGVAAGFDKNGVCIDSILKL
GFSFIEIGTITPRGQTGNAKPRIFRDVESRSIINSCGFNNMGCDKVTENLILFRKRQEED
KLLSKHIVGVSIGKNKDTVNIVDDLKYCINKIGRYADYIAINVSSPNTPGLRDNQEAGKL
KNIILSVKEEIDNLEKNNIMNDESTYNEDNKIVEKKNNFNKNNSHMMKDAKDNFLWFNTT
KKKPLVFVKLAPDLNQEQKKEIADVLLETNIDGMIISNTTTQINDIKSFENKKGGVSGAK
LKDISTKFICEMYNYTNKQIPIIASGGIFSGLDALEKIEAGASVCQLYSCLVFNGMKSAV
QIKRELNHLLYQRGYYNLKEAIGRKHSKS

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Drugs and Modes of Action

Top

Approved Drug(s)

[+] 4 Approved Drugs

Artemisinin

Drug Info

Approved

Malaria

[2]

Atovaquone

Drug Info

Approved

Fungal infection

[2]

Leflunomide

Drug Info

Approved

Arthritis

[3], [4], [5]

Teriflunomide

Drug Info

Approved

Hyperlipidaemia

[6]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Avastin+/-Tarceva

Drug Info

Phase 3

Non-small-cell lung cancer

[7]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 46 Inhibitor drugs

Artemisinin

Drug Info

[2]

Atovaquone

Drug Info

[1], [8], [9], [10]

Leflunomide

Drug Info

[11], [12], [13], [14]

Teriflunomide

Drug Info

[15], [16]

Avastin+/-Tarceva

Drug Info

[9]

1,4-Naphthoquinone

Drug Info

[9]

1-hydroxy-2-dodecyl-4(1H)quinolone

Drug Info

[17]

2-(2-bromo-2-naphthamido)benzoic acid

Drug Info

[18]

2-(2-naphthamido)benzoic acid

Drug Info

[18]

2-(3-(3,5-dichlorophenyl)ureido)benzoic acid

Drug Info

[19]

2-[(biphenyl-4-carbonyl)-amino]-benzoic acid

Drug Info

[18]

3,6,9,12,15-PENTAOXATRICOSAN-1-OL

Drug Info

[20]

3-hydroxy-2-phenylquinoline-4-carboxylic acid

Drug Info

[21]

5,8-hydroxy-naphthoquinone

Drug Info

[9]

5-Fluoro orotate

Drug Info

[22]

8-aminoquinolines

Drug Info

[10]

Acetate Ion

Drug Info

[23]

Antimycin A

Drug Info

[24]

Antiproliferative Agent A771726

Drug Info

[23]

B-Octylglucoside

Drug Info

[23]

Cinchoninic acid

Drug Info

[9]

Cyanide

Drug Info

[24]

Decylamine-N,N-Dimethyl-N-Oxide

Drug Info

[23]

Dichloroally-lawsone

Drug Info

[9]

Dichloroallyl lawsone

Drug Info

[25]

Diethyl 2-((biphenyl-3-ylamino)methylene)malonate

Drug Info

[26]

Dihydroorotate

Drug Info

[27]

DSM1

Drug Info

[28]

DSM2

Drug Info

[28]

Ethyl 3-(biphenyl-3-ylamino)-2-cyanoacrylate

Drug Info

[26]

GNF-PF-85

Drug Info

[29]

Isoxazol

Drug Info

[9]

Lauryl Dimethylamine-N-Oxide

Drug Info

[23]

LY214352

Drug Info

[30]

N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide

Drug Info

[26]

N-(4-bromo-2-methylphenyl)-2-naphthamide

Drug Info

[26]

N-(Biphenyl-4-yl)-2-cyano-3-hydroxybut-2-enamide

Drug Info

[31]

NSC 665564

Drug Info

[32]

Orotate

Drug Info

[22]

Orotic acid

Drug Info

[27]

Plumbagin

Drug Info

[9]

Polyporic acid

Drug Info

[9]

Redoxal

Drug Info

[25], [33]

Salicylhydroxamic acid

Drug Info

[24]

Triazine

Drug Info

[9]

Undecylamine-n,n-dimethyl-n-oxide

Drug Info

[20]

Drug Binding Sites of Target

Top

Ligand Name: Teriflunomide

Ligand Info

Structure Description

Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor

PDB:1TV5

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

[34]

PDB Sequence

FESYNPEFFL

¹⁶⁷

YDIFLKFCLK

¹⁷⁷

YIDGEICHDL

¹⁸⁷

FLLLGKYNIL

¹⁹⁷

PYDTSNDSIY

²⁰⁷

ACTNIKHLDF

²¹⁷

INPFGVAAGF

²²⁷

DKNGVCIDSI

²³⁷

LKLGFSFIEI

²⁴⁷

GTITPRGQTG

²⁵⁷

NAKPRIFRDV

²⁶⁷

ESRSIINSCG

²⁷⁷

FNNMGCDKVT

²⁸⁷

ENLILFRKRQ

²⁹⁷

EEDKLLSKHI

³⁰⁷

VGVSIGKNKD

³¹⁷

TVNIVDDLKY

³²⁷

CINKIGRYAD

³³⁷

YIAINVSSPN

³⁴⁷

TPGLRDNQEA

³⁵⁷

GKLKNIILSV

³⁶⁷

KEEIDNLEFL

⁴¹⁵

WFNTTKKKPL

⁴²⁵

VFVKLAPDLN

⁴³⁵

QEQKKEIADV

⁴⁴⁵

LLETNIDGMI

⁴⁵⁵

ISNTTTQIND

⁴⁶⁵

IKSFENKKGG

⁴⁷⁵

VSGAKLKDIS

⁴⁸⁵

TKFICEMYNY

⁴⁹⁵

TNKQIPIIAS

⁵⁰⁵

GGIFSGLDAL

⁵¹⁵

EKIEAGASVC

⁵²⁵

QLYSCLVFNG

⁵³⁵

MKSAVQIKRE

⁵⁴⁵

LNHLLYQRGY

⁵⁵⁵

YNLKEAIGRK

⁵⁶⁵

Residue

Distance (Å)

TYR168

4.421

PHE171

3.386

LEU172

3.663

CYS175

4.226

LEU176

4.868

GLY181

3.363

GLU182

4.710

CYS184

3.263

HIS185

2.777

PHE188

3.468

Residue

Distance (Å)

PHE227

3.776

ILE263

3.681

ARG265

2.898

ILE272

4.812

TYR528

2.686

LEU531

4.301

VAL532

3.316

GLY535

3.222

MET536

3.143

Ligand Name: 3,6,9,12,15-PENTAOXATRICOSAN-1-OL

Ligand Info

Structure Description

Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor

PDB:1TV5

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

[34]

PDB Sequence

FESYNPEFFL

¹⁶⁷

YDIFLKFCLK

¹⁷⁷

YIDGEICHDL

¹⁸⁷

FLLLGKYNIL

¹⁹⁷

PYDTSNDSIY

²⁰⁷

ACTNIKHLDF

²¹⁷

INPFGVAAGF

²²⁷

DKNGVCIDSI

²³⁷

LKLGFSFIEI

²⁴⁷

GTITPRGQTG

²⁵⁷

NAKPRIFRDV

²⁶⁷

ESRSIINSCG

²⁷⁷

FNNMGCDKVT

²⁸⁷

ENLILFRKRQ

²⁹⁷

EEDKLLSKHI

³⁰⁷

VGVSIGKNKD

³¹⁷

TVNIVDDLKY

³²⁷

CINKIGRYAD

³³⁷

YIAINVSSPN

³⁴⁷

TPGLRDNQEA

³⁵⁷

GKLKNIILSV

³⁶⁷

KEEIDNLEFL

⁴¹⁵

WFNTTKKKPL

⁴²⁵

VFVKLAPDLN

⁴³⁵

QEQKKEIADV

⁴⁴⁵

LLETNIDGMI

⁴⁵⁵

ISNTTTQIND

⁴⁶⁵

IKSFENKKGG

⁴⁷⁵

VSGAKLKDIS

⁴⁸⁵

TKFICEMYNY

⁴⁹⁵

TNKQIPIIAS

⁵⁰⁵

GGIFSGLDAL

⁵¹⁵

EKIEAGASVC

⁵²⁵

QLYSCLVFNG

⁵³⁵

MKSAVQIKRE

⁵⁴⁵

LNHLLYQRGY

⁵⁵⁵

YNLKEAIGRK

⁵⁶⁵

Residue

Distance (Å)

LEU167

4.021

TYR168

4.186

ASP169

3.386

ILE170

3.394

PHE171

3.552

LEU172

3.624

LYS173

2.718

PHE174

3.513

Residue

Distance (Å)

LEU176

4.521

LYS177

4.100

TYR178

4.217

LEU191

3.782

ILE196

3.545

PHE533

4.715

MET536

4.383

LYS537

4.828

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 Similarity Proteins

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 Similarity Proteins

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

Drug Property Profile of Target

Top

(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

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 2 KEGG Pathways

Pyrimidine metabolism

Metabolic pathways

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Pyrimidine Metabolism

Reactome

[+] 1 Reactome Pathways

Pyrimidine biosynthesis

WikiPathways

[+] 1 WikiPathways

Metabolism of nucleotides

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 2004 Apr;13(4):1031-42.

REF 2

The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6825).

REF 4

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

REF 5

New drugs in development for the treatment of endometriosis. Expert Opin Investig Drugs. 2008 Aug;17(8):1187-202.

REF 6

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

REF 7

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

REF 8

Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob Agents Chemother. 2000 Mar;44(3):713-9.

REF 9

Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact. 2000 Jan 3;124(1):61-76.

REF 10

The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase. Exp Parasitol. 1994 Aug;79(1):50-6.

REF 11

Identification and characterization of potential new therapeutic targets in inflammatory and autoimmune diseases. Eur J Biochem. 1999 Dec;266(3):1184-91.

REF 12

Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase. Protein Expr Purif. 1998 Aug;13(3):414-22.

REF 13

Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplant Proc. 1996 Dec;28(6):3088-91.

REF 14

Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol. 1995 Sep 7;50(6):861-7.

REF 15

Expression and characterization of E. coli-produced soluble, functional human dihydroorotate dehydrogenase: a potential target for immunosuppression. J Mol Microbiol Biotechnol. 1999 Aug;1(1):183-8.

REF 16

Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol. 1998 Nov 1;56(9):1259-64.

REF 17

Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors. Bioorg Med Chem Lett. 2009 Feb 1;19(3):972-5.

REF 18

The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett. 2006 Jan 1;16(1):88-92.

REF 19

Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures. Bioorg Med Chem Lett. 2010 Mar 15;20(6):1981-4.

REF 20

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 21

Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists. J Med Chem. 2007 Jan 11;50(1):21-39.

REF 22

Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase. Biochem Pharmacol. 1992 Mar 17;43(6):1295-301.

REF 23

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 24

Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother. 1995 Feb;39(2):325-8.

REF 25

Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J Biol Chem. 2002 Nov 1;277(44):41827-34.

REF 26

Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J Med Chem. 2007 Jan 25;50(2):186-91.

REF 27

Structure-activity relationships of pyrimidines as dihydroorotate dehydrogenase inhibitors. Biochem Pharmacol. 1988 Oct 15;37(20):3807-16.

REF 28

Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets. 2010 Jun;10(3):226-39.

REF 29

Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falcipa... J Med Chem. 2008 Jun 26;51(12):3649-53.

REF 30

Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach. Curr Genet. 1996 Jul 31;30(2):159-65.

REF 31

Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases. J Med Chem. 2009 May 14;52(9):2683-93.

REF 32

Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar. Biochem Biophys Res Commun. 1996 Jun 25;223(3):654-9.

REF 33

Redoxal as a new lead structure for dihydroorotate dehydrogenase inhibitors: a kinetic study of the inhibition mechanism. FEBS Lett. 2000 Feb 4;467(1):27-30.

REF 34

Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr D Biol Crystallogr. 2006 Mar;62(Pt 3):312-23.

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