Therapeutic Targets Database
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TTD Target ID: TTDS00208

Target Information
NameDihydrofolate reductase    
Type of targetSuccessful target    
DiseaseAutoimmune diseases    [1]
Bacterial infections    [2][3][4]
Cancer, unspecific    [3][5][6]
Chagas' disease    [7]
Fungal diseases    [1]
Inflammation    [8]
Leishmania infections    [9][10][11]
Leprosy, unspecified    [12]
Malaria    [2][13][14]
Microbial infections    [1][15]
P. carinii pneumonia    [16][17][18]
Parasitic diseases    [1]
Toxoplasma infections    [17][19][18]
Trypanosomatid infections    [9][10]
Tuberculosis    [20][21][1]
Drug(s)AminopterinApprovedLeukemia[22][23]
ChlorproguanilApprovedMalaria[24]
MCB-3837ApprovedMalaria and Bacterial infections[24][25]
PralatrexateApprovedPeripheral T cell lymphoma[26]
ProguanilApprovedMalaria[27]
ProquanilApprovedMalaria[24]
PyrimethamineApprovedAcute malaria[13][27][28]
TrimethoprimApprovedUrinary tract infections[29]
TrimetrexateApprovedPneumocystis pneumonia (PCP)[16][18]
IclaprimPhase IIIBacterial infections[25]
MetoprineDiscontinuedAdvanced cancer[30]
BioChemical ClassHydrolases acting on carbon-nitrogen bonds    
EC NumberEC 1.5.1.3
PathwayFolate biosynthesis
Glyoxylate and dicarboxylate metabolism
Metabolic pathways
Methionine metabolism
One carbon pool by folate
UniProt IDO33305
P00374
P00379
P0ABQ4
P13922
P16184
Q27793
Q8I372
Q9HBH1
PDB Structure1DF7; 1BOZ; 1DDR; 1J3I; 1CD2; 2H2Q; 1JYM; 3G5K.    
SequenceMMEQVCDVFDIYAICACCKVESKNEGKKNEVFNNYTFRGLGNKGVLPWKCNSLDMKYFRA VTTYVNESKYEKLKYKRCKYLNKETVDNVNDMPNSKKLQNVVVMGRTNWESIPKKFKPLS NRINVILSRTLKKEDFDEDVYIINKVEDLIVLLGKLNYYKCFIIGGSVVYQEFLEKKLIK KIYFTRINSTYECDVFFPEINENEYQIISVSDVYTSNNTTLDFIIYKKTNNKMLNEQNCI KGEEKNNDMPLKNDDKDTCHMKKLTEFYKNVDKYKINYENDDDDEEEDDFVYFNFNKEKE EKNKNSIHPNDFQIYNSLKYKYHPEYQYLNIIYDIMMNGNKQSDRTGVGVLSKFGYIMKF DLSQYFPLLTTKKLFLRGIIEELLWFIRGETNGNTLLNKNVRIWEANGTREFLDNRKLFH REVNDLGPIYGFQWRHFGAEYTNMYDNYENKGVDQLKNIINLIKNDPTSRRILLCAWNVK DLDQMALPPCHILCQFYVFDGKLSCIMYQRSCDLGLGVPFNIASYSIFTHMIAQVCNLQP AQFIHVLGNAHVYNNHIDSLKIQLNRIPYPFPTLKLNPDIKNIEDFTISDFTIQNYVHHE KISMDMAA
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor2'-Monophosphoadenosine 5'-Diphosphoribose[31]
2'-Monophosphoadenosine-5'-Diphosphate[31]
2,4-diamino triazine[32]
2- (N-Morpholino)-Ethanesulfonic Acid[31]
2-Allylthio-3-benzyl-6-nitro-quinazolin-4 (3H)-one[33]
2-Allylthio-6-amino-3-benzyl-quinazolin-4 (3H)-one[33]
3-Benzyl-2-ethylthio-6-nitro-quinazolin-4 (3H)-one[33]
3-Phenylsulfanylmethyl-quinoxaline-5,7-diamine[34]
3-benzyl-2-mercapto-6-nitroquinazolin-4 (3H)-one[33]
4- (2,6-diamino-9H-purin-8-yl)-2,6-dimethoxyphenol[35]
5,10-Dideazatetrahydrofolic Acid[31]
5- ([36]
5- (2-fluorobenzyloxy)quinazoline-2,4-diamine[37]
5- (4-Methoxyphenoxy)-2,4-Quinazolinediamine[31]
5-Chloryl-2,4,6-Quinazolinetriamine[31]
5-Formyl-6-Hydrofolic Acid[31]
5-Phenethyl-quinazoline-2,4-diamine[36]
5-Phenylsulfanyl-2,4-Quinazolinediamine[31]
5-Phenylsulfanyl-quinazoline-2,4-diamine[38]
5-p-Tolylsulfanyl-quinazoline-2,4-diamine[38]
6,7-Diphenyl-pteridine-2,4-diamine[39]
6- (2-Phenylsulfanyl-ethyl)-pteridine-2,4-diamine[39]
6-Phenylaminomethyl-quinazoline-2,4-diamine[40]
6-Phenylsulfanylmethyl-pteridine-2,4-diamine[41]
6-m-Tolyl-pteridine-2,4,7-triamine[39]
7-Methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine[42]
7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine[42]
8- (2,3,4-trimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (2,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (2,4,6-trimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (2,4-dimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (2,5-dimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (2,6-Dichloro-phenyl)-9H-purine-2,6-diamine[43]
8- (3,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (3,4-dichlorophenyl)-9H-purine-2,6-diamine[35]
8- (3,4-dimethoxyphenyl)-9H-purine-2,6-diamine[35]
8- (3,5-dimethoxyphenyl)-9H-purine-2,6-diamine[35]
8-Pyridin-4-yl-9H-purine-2,6-diamine[43]
8-benzyl-9H-purine-2,6-diamine[35]
Aminopterin[22][23]
Beta-Mercaptoethanol[31]
Biopterin[31]
Br-WR99210[1]
Brodimoprim-4,6-Dicarboxylate[31]
Bromo-WR99210[31]
CB-3717[44]
Chlorproguanil[24]
Cycloguanil[45][27][28]
Cycloguanil[46]
Dihydrofolic Acid[31]
Edatrexate[22]
Epiroprim[12]
Furo[2,3d]Pyrimidine Antifolate[31]
GNF-PF-173[47]
GNF-PF-607[48]
MCB-3837[24][25]
Methotrexate[6][5][22]
Metoprine[30]
N*6*-Benzyl-quinazoline-2,4,6-triamine[48]
NB-3040[49]
NB3178[49]
NB3322[49]
PDDF[50]
PIRITREXIM[51]
PREMETREXED[52]
Pergularinine[15]
Pralatrexate[26]
Proguanil[27]
Proquanil[24]
Pyrimethamine[13][27][28]
Sri-9439[53]
Sri-9662[31]
Trimethoprim[29]
Trimetrexate[16][18]
Tylophorinidine[15]
WR-99210[54]
WR99210[20][27]
derivative of methotrexate[55]
derivative of methotrexate[55]
derivative of methotrexate[55]
derivative of methotrexate[55]
BinderIclaprim[25]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs. J Mol Biol. 2000 Jan 14;295(2):307-23. To Reference
Ref 2Resistance to trimethoprim and sulfonamides. Vet Res. 2001 May-Aug;32(3-4):261-73. To Reference
Ref 3Design of dihydrofolate reductase inhibitors from X-ray crystal structures. Fed Proc. 1986 Nov;45(12):2765-72. To Reference
Ref 4Partial resistance of E. coli mutants against 2, 4-diamino-5-benzylpyrimidines by interactions with bacterial membrane lipopolysaccharides. Derivation of quantitative structure-binding relationships. Eur J Med Chem. 2000 Jun;35(6):619-34. To Reference
Ref 5Deaza analogs of folic acid as antitumor agents. Curr Pharm Des. 2003;9(31):2615-25. To Reference
Ref 6Anticancer antifolates: current status and future directions. Curr Pharm Des. 2003;9(31):2593-613. To Reference
Ref 7Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase. Eur J Med Chem. 2001 May;36(5):395-405. To Reference
Ref 8Dihydrofolate reductase as a therapeutic target. FASEB J. 1990 May;4(8):2441-52. To Reference
Ref 9Synthesis and testing of 5-benzyl-2,4-diaminopyrimidines as potential inhibitors of leishmanial and trypanosomal dihydrofolate reductase. J Enzyme Inhib Med Chem. 2002 Oct;17(5):293-302. To Reference
Ref 10Dihydrofolate reductase: a potential drug target in trypanosomes and leishmania. J Comput Aided Mol Des. 1998 May;12(3):241-57. To Reference
Ref 11Pterin and folate reduction by the Leishmania tarentolae H locus short-chain dehydrogenase/reductase PTR1. Arch Biochem Biophys. 1997 Jun 15;342(2):197-202. To Reference
Ref 12In vivo activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with dapsone, against Mycobacterium leprae. Int J Antimicrob Agents. 2002 Jan;19(1):71-4. To Reference
Ref 13Structure of Plasmodium vivax dihydrofolate reductase determined by homology modeling and molecular dynamics refinement. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3257-60. To Reference
Ref 14Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. J Med Chem. 2003 Jul 3;46(14):2834-45. To Reference
Ref 15Inhibition of dihydrofolate reductase and cell growth activity by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine: the in vitro cytotoxicity of these plant alkaloids and their potential as antimicrobial and anticancer agents. Toxicol In Vitro. 2000 Feb;14(1):53-9. To Reference
Ref 16Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase. Antimicrob Agents Chemother. 2000 Nov;44(11):3092-6. To Reference
Ref 176-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents. J Med Chem. 1998 Nov 5;41(23):4533-41. To Reference
Ref 18Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases. J Med Chem. 1998 Apr 23;41(9):1409-16. To Reference
Ref 19Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem. 1998 Aug 27;41(18):3426-34. To Reference
Ref 20Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase. Antimicrob Agents Chemother. 2002 Nov;46(11):3362-9. To Reference
Ref 21A proposed model of Mycobacterium avium complex dihydrofolate reductase and its utility for drug design. Org Biomol Chem. 2003 Apr 21;1(8):1315-22. To Reference
Ref 22Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99. To Reference
Ref 23vestigial suppressor genes and resistance to aminopterin in Drosophila melanogaster. Heredity. 1992 Nov;69 ( Pt 5):473-7. To Reference
Ref 24The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71. To Reference
Ref 25How many modes of action should an antibiotic have? Curr Opin Pharmacol. 2008 Oct;8(5):564-73. Epub 2008 Jul 30. To Reference
Ref 26Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92. To Reference
Ref 27Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6. To Reference
Ref 28Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol Biochem Parasitol. 1997 Mar;85(1):25-40. To Reference
Ref 29Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus. Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):751-7. Epub 2009 Jul 10. To Reference
Ref 30Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34. Epub 2006 Apr 13. To Reference
Ref 31Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 32Ab initio studies of 2,4-diamino triazine and its complexes with ligands: a model for inhibitor-active site interactions of dihydrofolate reductase. Cancer Invest. 1994;12(5):469-76. To Reference
Ref 33Bioorg Med Chem. 2010 Apr 15;18(8):2849-63. Epub 2010 Mar 12.Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. To Reference
Ref 34J Med Chem. 1995 Nov 24;38(24):4739-59.New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii. To Reference
Ref 35Bioorg Med Chem. 2010 Feb 15;18(4):1684-701. Epub 2010 Jan 6.CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified cross-validated r(2)-guided region selection (q(2)-GRS) routine and its initial application. To Reference
Ref 36J Med Chem. 1995 Mar 3;38(5):745-52.2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii. To Reference
Ref 37J Med Chem. 2008 Feb 14;51(3):449-69. Epub 2008 Jan 19.Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. To Reference
Ref 38J Med Chem. 2001 Aug 30;44(18):2928-32.X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor. To Reference
Ref 39J Med Chem. 2003 Apr 24;46(9):1726-36.Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. To Reference
Ref 40J Med Chem. 2003 Jul 31;46(16):3455-62.Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model. To Reference
Ref 41J Med Chem. 1996 Apr 26;39(9):1836-45.Nonclassical 2,4-diamino-8-deazafolate analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma gondii. To Reference
Ref 42J Med Chem. 1996 Feb 16;39(4):892-903.High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size. To Reference
Ref 43J Med Chem. 1997 Sep 12;40(19):3032-9.Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii. To Reference
Ref 44J Med Chem. 2009 Aug 13;52(15):4892-902.Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. To Reference
Ref 45Gene organization of a Plasmodium falciparum serine hydroxymethyltransferase and its functional expression in Escherichia coli. Mol Biochem Parasitol. 2000 Oct;110(2):283-91. To Reference
Ref 46Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40. To Reference
Ref 47J Med Chem. 1988 Jan;31(1):181-5.Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin. To Reference
Ref 48J Med Chem. 2005 Mar 10;48(5):1448-69.CoMFA and CoMSIA analyses of Pneumocystis carinii dihydrofolate reductase, Toxoplasma gondii dihydrofolate reductase, and rat liver dihydrofolate reductase. To Reference
Ref 49Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98. To Reference
Ref 50J Med Chem. 2005 Nov 17;48(23):7215-22.Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents. To Reference
Ref 51J Med Chem. 2008 Oct 9;51(19):6195-200. Epub 2008 Sep 5.N9-substituted 2,4-diaminoquinazolines: synthesis and biological evaluation of lipophilic inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase. To Reference
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