Target Information
| Target General Information | Top | |||||
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| Target ID |
T01318
(Former ID: TTDS00059)
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| Target Name |
Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase)
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| 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
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Fungal infection [ICD-11: 1F29-1F2F] | |||||
| 2 | Hyper-lipoproteinaemia [ICD-11: 5C80] | |||||
| 3 | Malaria [ICD-11: 1F40-1F45] | |||||
| 4 | Multiple sclerosis [ICD-11: 8A40] | |||||
| 5 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| Function |
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Click to Show/Hide
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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 |
MISKLKPQFMFLPKKHILSYCRKDVLNLFEQKFYYTSKRKESNNMKNESLLRLINYNRYY
NKIDSNNYYNGGKILSNDRQYIYSPLCEYKKKINDISSYVSVPFKINIRNLGTSNFVNNK KDVLDNDYIYENIKKEKSKHKKIIFLLFVSLFGLYGFFESYNPEFFLYDIFLKFCLKYID GEICHDLFLLLGKYNILPYDTSNDSIYACTNIKHLDFINPFGVAAGFDKNGVCIDSILKL GFSFIEIGTITPRGQTGNAKPRIFRDVESRSIINSCGFNNMGCDKVTENLILFRKRQEED KLLSKHIVGVSIGKNKDTVNIVDDLKYCINKIGRYADYIAINVSSPNTPGLRDNQEAGKL KNIILSVKEEIDNLEKNNIMNDESTYNEDNKIVEKKNNFNKNNSHMMKDAKDNFLWFNTT KKKPLVFVKLAPDLNQEQKKEIADVLLETNIDGMIISNTTTQINDIKSFENKKGGVSGAK LKDISTKFICEMYNYTNKQIPIIASGGIFSGLDALEKIEAGASVCQLYSCLVFNGMKSAV QIKRELNHLLYQRGYYNLKEAIGRKHSKS Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Artemisinin | Drug Info | Approved | Malaria | [2] | |
| 2 | Atovaquone | Drug Info | Approved | Fungal infection | [2] | |
| 3 | Leflunomide | Drug Info | Approved | Arthritis | [3], [4], [5] | |
| 4 | Teriflunomide | Drug Info | Approved | Hyperlipidaemia | [6] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Avastin+/-Tarceva | Drug Info | Phase 3 | Non-small-cell lung cancer | [7] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 46 Inhibitor drugs | + | ||||
| 1 | Artemisinin | Drug Info | [2] | |||
| 2 | Atovaquone | Drug Info | [1], [8], [9], [10] | |||
| 3 | Leflunomide | Drug Info | [11], [12], [13], [14] | |||
| 4 | Teriflunomide | Drug Info | [15], [16] | |||
| 5 | Avastin+/-Tarceva | Drug Info | [9] | |||
| 6 | 1,4-Naphthoquinone | Drug Info | [9] | |||
| 7 | 1-hydroxy-2-dodecyl-4(1H)quinolone | Drug Info | [17] | |||
| 8 | 2-(2-bromo-2-naphthamido)benzoic acid | Drug Info | [18] | |||
| 9 | 2-(2-naphthamido)benzoic acid | Drug Info | [18] | |||
| 10 | 2-(3-(3,5-dichlorophenyl)ureido)benzoic acid | Drug Info | [19] | |||
| 11 | 2-[(biphenyl-4-carbonyl)-amino]-benzoic acid | Drug Info | [18] | |||
| 12 | 3,6,9,12,15-PENTAOXATRICOSAN-1-OL | Drug Info | [20] | |||
| 13 | 3-hydroxy-2-phenylquinoline-4-carboxylic acid | Drug Info | [21] | |||
| 14 | 5,8-hydroxy-naphthoquinone | Drug Info | [9] | |||
| 15 | 5-Fluoro orotate | Drug Info | [22] | |||
| 16 | 8-aminoquinolines | Drug Info | [10] | |||
| 17 | Acetate Ion | Drug Info | [23] | |||
| 18 | Antimycin A | Drug Info | [24] | |||
| 19 | Antiproliferative Agent A771726 | Drug Info | [23] | |||
| 20 | B-Octylglucoside | Drug Info | [23] | |||
| 21 | Cinchoninic acid | Drug Info | [9] | |||
| 22 | Cyanide | Drug Info | [24] | |||
| 23 | Decylamine-N,N-Dimethyl-N-Oxide | Drug Info | [23] | |||
| 24 | Dichloroally-lawsone | Drug Info | [9] | |||
| 25 | Dichloroallyl lawsone | Drug Info | [25] | |||
| 26 | Diethyl 2-((biphenyl-3-ylamino)methylene)malonate | Drug Info | [26] | |||
| 27 | Dihydroorotate | Drug Info | [27] | |||
| 28 | DSM1 | Drug Info | [28] | |||
| 29 | DSM2 | Drug Info | [28] | |||
| 30 | Ethyl 3-(biphenyl-3-ylamino)-2-cyanoacrylate | Drug Info | [26] | |||
| 31 | GNF-PF-85 | Drug Info | [29] | |||
| 32 | Isoxazol | Drug Info | [9] | |||
| 33 | Lauryl Dimethylamine-N-Oxide | Drug Info | [23] | |||
| 34 | LY214352 | Drug Info | [30] | |||
| 35 | N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide | Drug Info | [26] | |||
| 36 | N-(4-bromo-2-methylphenyl)-2-naphthamide | Drug Info | [26] | |||
| 37 | N-(Biphenyl-4-yl)-2-cyano-3-hydroxybut-2-enamide | Drug Info | [31] | |||
| 38 | NSC 665564 | Drug Info | [32] | |||
| 39 | Orotate | Drug Info | [22] | |||
| 40 | Orotic acid | Drug Info | [27] | |||
| 41 | Plumbagin | Drug Info | [9] | |||
| 42 | Polyporic acid | Drug Info | [9] | |||
| 43 | Redoxal | Drug Info | [25], [33] | |||
| 44 | Salicylhydroxamic acid | Drug Info | [24] | |||
| 45 | Triazine | Drug Info | [9] | |||
| 46 | Undecylamine-n,n-dimethyl-n-oxide | Drug Info | [20] | |||
| Drug Property Profile of Target | Top | |
|---|---|---|
| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||||||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
|---|---|---|---|---|---|---|
| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
|---|---|---|---|---|---|---|
| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Pyrimidine metabolism | |||||
| 2 | Metabolic pathways | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Pyrimidine Metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Pyrimidine biosynthesis | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Metabolism of nucleotides | |||||
| Target-Related Models and Studies | Top | |||||
|---|---|---|---|---|---|---|
| Target Validation | ||||||
| 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. | |||||
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