Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT3PQ2Y)

• DTT 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
• Gene Name: Malaria DHOdehase
• DTT Type: Successful target; [1]
• Related Disease:
  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]
• BioChemical Class: CH-CH donor oxidoreductase
• UniProt ID: PYRD_PLAF7
• TTD ID: T01318
• EC Number: EC 1.3.5.2
• Sequence:
  MISKLKPQFMFLPKKHILSYCRKDVLNLFEQKFYYTSKRKESNNMKNESLLRLINYNRYY
  NKIDSNNYYNGGKILSNDRQYIYSPLCEYKKKINDISSYVSVPFKINIRNLGTSNFVNNK
  KDVLDNDYIYENIKKEKSKHKKIIFLLFVSLFGLYGFFESYNPEFFLYDIFLKFCLKYID
  GEICHDLFLLLGKYNILPYDTSNDSIYACTNIKHLDFINPFGVAAGFDKNGVCIDSILKL
  GFSFIEIGTITPRGQTGNAKPRIFRDVESRSIINSCGFNNMGCDKVTENLILFRKRQEED
  KLLSKHIVGVSIGKNKDTVNIVDDLKYCINKIGRYADYIAINVSSPNTPGLRDNQEAGKL
  KNIILSVKEEIDNLEKNNIMNDESTYNEDNKIVEKKNNFNKNNSHMMKDAKDNFLWFNTT
  KKKPLVFVKLAPDLNQEQKKEIADVLLETNIDGMIISNTTTQINDIKSFENKKGGVSGAK
  LKDISTKFICEMYNYTNKQIPIIASGGIFSGLDALEKIEAGASVCQLYSCLVFNGMKSAV
  QIKRELNHLLYQRGYYNLKEAIGRKHSKS
• Function: Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
• Reactome Pathway: Pyrimidine biosynthesis (R-HSA-500753)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Artemisinin	DMOY7W3	Malaria	1F40-1F45	Approved	[2]
Atovaquone	DMY4UMW	Fungal infection	1F29-1F2F	Approved	[1], [3], [4], [5]
Leflunomide	DMR8ONJ	Arthritis	FA20	Approved	[6], [7], [8], [9]
Teriflunomide	DMQ2FKJ	Hyperlipidaemia	5C80	Approved	[10], [11]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Avastin+/-Tarceva	DMA86FL	Non-small-cell lung cancer	2C25.Y	Phase 3	[4]

41 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,4-Naphthoquinone	DMTCMH7	Discovery agent	N.A.	Investigative	[4]
1-hydroxy-2-dodecyl-4(1H)quinolone	DMGBSWP	Discovery agent	N.A.	Investigative	[12]
2-(2-bromo-2-naphthamido)benzoic acid	DMFK0GM	Discovery agent	N.A.	Investigative	[13]
2-(2-naphthamido)benzoic acid	DMN176Y	Discovery agent	N.A.	Investigative	[13]
2-(3-(3,5-dichlorophenyl)ureido)benzoic acid	DMM9WB0	Discovery agent	N.A.	Investigative	[14]
2-[(biphenyl-4-carbonyl)-amino]-benzoic acid	DMDT7SK	Discovery agent	N.A.	Investigative	[13]
3,6,9,12,15-PENTAOXATRICOSAN-1-OL	DMMVL5P	Discovery agent	N.A.	Investigative	[15]
3-hydroxy-2-phenylquinoline-4-carboxylic acid	DMIVDFW	Discovery agent	N.A.	Investigative	[16]
5,8-hydroxy-naphthoquinone	DM1SO62	Discovery agent	N.A.	Investigative	[4]
5-Fluoro orotate	DMLSC10	Discovery agent	N.A.	Investigative	[17]
8-aminoquinolines	DMN8QAF	Discovery agent	N.A.	Investigative	[5]
Acetate Ion	DMD08RH	Discovery agent	N.A.	Investigative	[18]
Antimycin A	DM2EMCW	Discovery agent	N.A.	Investigative	[19]
Antiproliferative Agent A771726	DM9THZE	Discovery agent	N.A.	Investigative	[18]
B-Octylglucoside	DMMO75G	Discovery agent	N.A.	Investigative	[18]
Cinchoninic acid	DMOJ917	Discovery agent	N.A.	Investigative	[4]
Cyanide	DMJE4HK	Discovery agent	N.A.	Investigative	[19]
Decylamine-N,N-Dimethyl-N-Oxide	DM2WEB9	Discovery agent	N.A.	Investigative	[18]
Dichloroally-lawsone	DMAU5VM	Discovery agent	N.A.	Investigative	[4]
Dichloroallyl lawsone	DMXGV63	Discovery agent	N.A.	Investigative	[20]
Diethyl 2-((biphenyl-3-ylamino)methylene)malonate	DM7YHBR	Discovery agent	N.A.	Investigative	[21]
Dihydroorotate	DM76BGZ	Discovery agent	N.A.	Investigative	[22]
DSM1	DM1LK0C	Malaria	1F40-1F45	Investigative	[23]
DSM2	DMZYQOB	Malaria	1F40-1F45	Investigative	[23]
Ethyl 3-(biphenyl-3-ylamino)-2-cyanoacrylate	DM5XYFN	Discovery agent	N.A.	Investigative	[21]
GNF-PF-85	DMB6FN7	Discovery agent	N.A.	Investigative	[24]
Isoxazol	DMXAD8E	Discovery agent	N.A.	Investigative	[4]
Lauryl Dimethylamine-N-Oxide	DM3W2OE	Discovery agent	N.A.	Investigative	[18]
LY214352	DMKZJVA	Discovery agent	N.A.	Investigative	[25]
N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide	DM9B1ID	Discovery agent	N.A.	Investigative	[21]
N-(4-bromo-2-methylphenyl)-2-naphthamide	DMSNZV1	Discovery agent	N.A.	Investigative	[21]
N-(Biphenyl-4-yl)-2-cyano-3-hydroxybut-2-enamide	DMSO7FW	Discovery agent	N.A.	Investigative	[26]
NSC 665564	DMX4DT7	Discovery agent	N.A.	Investigative	[27]
Orotate	DMMB29S	Discovery agent	N.A.	Investigative	[17]
Orotic acid	DMP6BSH	Discovery agent	N.A.	Investigative	[22]
Plumbagin	DM9BS50	Discovery agent	N.A.	Investigative	[4]
Polyporic acid	DMN6Q4E	Discovery agent	N.A.	Investigative	[4]
Redoxal	DM2S496	Discovery agent	N.A.	Investigative	[20], [28]
Salicylhydroxamic acid	DMGLSPC	Discovery agent	N.A.	Investigative	[19]
Triazine	DM8LYSB	Discovery agent	N.A.	Investigative	[4]
Undecylamine-n,n-dimethyl-n-oxide	DM4AYC2	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	9.02E-04	-0.61	-2.46

References

• [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.
• [2] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [3] 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.
• [4] 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.
• [5] The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase. Exp Parasitol. 1994 Aug;79(1):50-6.
• [6] Identification and characterization of potential new therapeutic targets in inflammatory and autoimmune diseases. Eur J Biochem. 1999 Dec;266(3):1184-91.
• [7] Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase. Protein Expr Purif. 1998 Aug;13(3):414-22.
• [8] Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplant Proc. 1996 Dec;28(6):3088-91.
• [9] Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol. 1995 Sep 7;50(6):861-7.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett. 2006 Jan 1;16(1):88-92.
• [14] 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.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists. J Med Chem. 2007 Jan 11;50(1):21-39.
• [17] Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase. Biochem Pharmacol. 1992 Mar 17;43(6):1295-301.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother. 1995 Feb;39(2):325-8.
• [20] Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J Biol Chem. 2002 Nov 1;277(44):41827-34.
• [21] Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J Med Chem. 2007 Jan 25;50(2):186-91.
• [22] Structure-activity relationships of pyrimidines as dihydroorotate dehydrogenase inhibitors. Biochem Pharmacol. 1988 Oct 15;37(20):3807-16.
• [23] Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets. 2010 Jun;10(3):226-39.
• [24] 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.
• [25] Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach. Curr Genet. 1996 Jul 31;30(2):159-65.
• [26] 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.
• [27] 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.
• [28] 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.