Target Information
| Target General Information | Top | |||||
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| Target ID |
T89515
(Former ID: TTDS00208)
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| Target Name |
Polypeptide deformylase (PDF)
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| Synonyms |
PDF
Click to Show/Hide
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| Gene Name |
PDF
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 6 Target-related Diseases | + | ||||
| 1 | Anxiety disorder [ICD-11: 6B00-6B0Z] | |||||
| 2 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| 3 | Malaria [ICD-11: 1F40-1F45] | |||||
| 4 | Mature T-cell lymphoma [ICD-11: 2A90] | |||||
| 5 | Psoriasis [ICD-11: EA90] | |||||
| 6 | Toxoplasmosis [ICD-11: 1F57] | |||||
| Function |
Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
Click to Show/Hide
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| BioChemical Class |
CH-NH donor oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.1.88
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| Sequence |
MARLWGALSLWPLWAAVPWGGAAAVGVRACSSTAAPDGVEGPALRRSYWRHLRRLVLGPP
EPPFSHVCQVGDPVLRGVAAPVERAQLGGPELQRLTQRLVQVMRRRRCVGLSAPQLGVPR QVLALELPEALCRECPPRQRALRQMEPFPLRVFVNPSLRVLDSRLVTFPEGCESVAGFLA CVPRFQAVQISGLDPNGEQVVWQASGWAARIIQHEMDHLQGCLFIDKMDSRTFTNVYWMK VND Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 7 Approved Drugs | + | ||||
| 1 | Chlorproguanil | Drug Info | Approved | Malaria | [1] | |
| 2 | MCB-3837 | Drug Info | Approved | Malaria | [2] | |
| 3 | Meprobamate | Drug Info | Approved | Malaria | [1], [3] | |
| 4 | Pralatrexate | Drug Info | Approved | Breast cancer | [3], [4], [5] | |
| 5 | Proguanil | Drug Info | Approved | Malaria | [6] | |
| 6 | Trimetrexate | Drug Info | Approved | Toxoplasmosis | [3] | |
| 7 | Ustekinumab | Drug Info | Approved | Plaque psoriasis | [7], [5] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | LY333531 | Drug Info | Phase 2 | Solid tumour/cancer | [8] | |
| 2 | Metoprine | Drug Info | Phase 2 | Advanced cancer | [9], [10] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Aminopterin | Drug Info | Withdrawn from market | leukaemia | [11] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 66 Inhibitor drugs | + | ||||
| 1 | Chlorproguanil | Drug Info | [1] | |||
| 2 | MCB-3837 | Drug Info | [1], [2] | |||
| 3 | Meprobamate | Drug Info | [1] | |||
| 4 | Pralatrexate | Drug Info | [5] | |||
| 5 | Proguanil | Drug Info | [12] | |||
| 6 | Trimetrexate | Drug Info | [13], [14] | |||
| 7 | Ustekinumab | Drug Info | [12], [15] | |||
| 8 | LY333531 | Drug Info | [16] | |||
| 9 | Metoprine | Drug Info | [17] | |||
| 10 | Aminopterin | Drug Info | [18], [19] | |||
| 11 | 2'-Monophosphoadenosine 5'-Diphosphoribose | Drug Info | [20] | |||
| 12 | 2'-Monophosphoadenosine-5'-Diphosphate | Drug Info | [20] | |||
| 13 | 2-(N-Morpholino)-Ethanesulfonic Acid | Drug Info | [20] | |||
| 14 | 2-Allylthio-3-benzyl-6-nitro-quinazolin-4(3H)-one | Drug Info | [21] | |||
| 15 | 2-Allylthio-6-amino-3-benzyl-quinazolin-4(3H)-one | Drug Info | [21] | |||
| 16 | 2-Sulfhydryl-Ethanol | Drug Info | [20] | |||
| 17 | 3-Benzyl-2-ethylthio-6-nitro-quinazolin-4(3H)-one | Drug Info | [21] | |||
| 18 | 3-benzyl-2-mercapto-6-nitroquinazolin-4(3H)-one | Drug Info | [21] | |||
| 19 | 3-Phenylsulfanylmethyl-quinoxaline-5,7-diamine | Drug Info | [22] | |||
| 20 | 4-(2,6-diamino-9H-purin-8-yl)-2,6-dimethoxyphenol | Drug Info | [23] | |||
| 21 | 5-((E)-Styryl)-quinazoline-2,4-diamine | Drug Info | [24] | |||
| 22 | 5-(2-fluorobenzyloxy)quinazoline-2,4-diamine | Drug Info | [25] | |||
| 23 | 5-(4-Methoxyphenoxy)-2,4-Quinazolinediamine | Drug Info | [20] | |||
| 24 | 5-Chloryl-2,4,6-Quinazolinetriamine | Drug Info | [20] | |||
| 25 | 5-Formyl-6-Hydrofolic Acid | Drug Info | [20] | |||
| 26 | 5-p-Tolylsulfanyl-quinazoline-2,4-diamine | Drug Info | [26] | |||
| 27 | 5-Phenethyl-quinazoline-2,4-diamine | Drug Info | [24] | |||
| 28 | 5-Phenylsulfanyl-2,4-Quinazolinediamine | Drug Info | [20], [26] | |||
| 29 | 6,7-Diphenyl-pteridine-2,4-diamine | Drug Info | [27] | |||
| 30 | 6-(2-Phenylsulfanyl-ethyl)-pteridine-2,4-diamine | Drug Info | [27] | |||
| 31 | 6-m-Tolyl-pteridine-2,4,7-triamine | Drug Info | [27] | |||
| 32 | 6-Phenylaminomethyl-quinazoline-2,4-diamine | Drug Info | [28] | |||
| 33 | 6-Phenylsulfanylmethyl-pteridine-2,4-diamine | Drug Info | [29] | |||
| 34 | 7-Methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine | Drug Info | [30] | |||
| 35 | 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine | Drug Info | [30] | |||
| 36 | 8-(2,3,4-trimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 37 | 8-(2,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 38 | 8-(2,4,6-trimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 39 | 8-(2,4-dimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 40 | 8-(2,5-dimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 41 | 8-(2,6-Dichloro-phenyl)-9H-purine-2,6-diamine | Drug Info | [31] | |||
| 42 | 8-(3,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 43 | 8-(3,4-dichlorophenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 44 | 8-(3,4-dimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 45 | 8-(3,5-dimethoxyphenyl)-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 46 | 8-benzyl-9H-purine-2,6-diamine | Drug Info | [23] | |||
| 47 | 8-Pyridin-4-yl-9H-purine-2,6-diamine | Drug Info | [31] | |||
| 48 | Biopterin | Drug Info | [20] | |||
| 49 | Brodimoprim-4,6-Dicarboxylate | Drug Info | [20] | |||
| 50 | Bromo-WR99210 | Drug Info | [20] | |||
| 51 | Cycloguanil | Drug Info | [6] | |||
| 52 | DDATHF | Drug Info | [20] | |||
| 53 | Dihydrofolic Acid | Drug Info | [20] | |||
| 54 | Edatrexate | Drug Info | [18] | |||
| 55 | Furo[2,3d]Pyrimidine Antifolate | Drug Info | [20] | |||
| 56 | GNF-PF-173 | Drug Info | [32] | |||
| 57 | GNF-PF-607 | Drug Info | [33] | |||
| 58 | N*6*-Benzyl-quinazoline-2,4,6-triamine | Drug Info | [33] | |||
| 59 | NB3178 | Drug Info | [34] | |||
| 60 | NB3322 | Drug Info | [34] | |||
| 61 | Pergularinine | Drug Info | [35] | |||
| 62 | PREMETREXED | Drug Info | [36] | |||
| 63 | Ro 5-4864 | Drug Info | [34] | |||
| 64 | Sri-9439 | Drug Info | [37] | |||
| 65 | Sri-9662 | Drug Info | [20] | |||
| 66 | Tylophorinidine | Drug Info | [35] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Actinonin | Ligand Info | |||||
| Structure Description | Structure and activity of human mitochondrial peptide deformylase, a novel cancer target | PDB:3G5K | ||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [38] |
| PDB Sequence |
HMSFSHVCQV
12 GDPVLRGVAA22 PVERAQLGGP32 ELQRLTQRLV42 QVMRRRRCVG52 LSAPQLGVPR 62 QVLALELPEA72 LCRECPPRQR82 ALRQMEPFPL92 RVFVNPSLRV102 LDSRLVTFPE 112 GCESVAGFLA122 CVPRFQAVQI132 SGLDPNGEQV142 VWQASGWAAR152 IIQHEMDHLQ 162 GCLFIDKMDS172 RTFTNVYWMK182 VND
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ARG49
4.673
CYS50
3.511
VAL51
3.263
GLY52
2.896
LEU53
4.176
SER54
4.815
GLN57
2.949
ARG85
4.640
PRO111
2.698
GLU112
3.465
GLY113
2.920
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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 Similarity Proteins
Human Tissue Distribution
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There is no similarity protein (E value < 0.005) for this target
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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.
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (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 | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Pathwhiz Pathway | [+] 2 Pathwhiz Pathways | + | ||||
| 1 | Folate Metabolism | |||||
| 2 | Pterine Biosynthesis | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | E2F mediated regulation of DNA replication | |||||
| 2 | Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation | |||||
| 3 | Metabolism of folate and pterines | |||||
| 4 | G1/S-Specific Transcription | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71. | |||||
| REF 2 | How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73. | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | 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: 6840). | |||||
| REF 5 | Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92. | |||||
| REF 6 | Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40. | |||||
| REF 7 | 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: 6885). | |||||
| REF 8 | ClinicalTrials.gov (NCT00482976) Effect of LY333531 on Vascular and Neural Functions. U.S. National Institutes of Health. | |||||
| REF 9 | 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: 7412). | |||||
| REF 10 | ClinicalTrials.gov (NCT01579110) Efficacy and Safety of Levamisole Combined With Standard Prednisolone in Warm Antibody Autoimmune Hemolytic Anemia.. U.S. National Institutes of Health. | |||||
| REF 11 | Drug information of Aminopterin, Health Canada, 2007. | |||||
| REF 12 | Transformation 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. | |||||
| REF 13 | Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase. Antimicrob Agents Chemother. 2000 Nov;44(11):3092-6. | |||||
| REF 14 | Synthesis 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. | |||||
| REF 15 | Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase. Antimicrob Agents Chemother. 2002 Nov;46(11):3362-9. | |||||
| REF 16 | Three-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. | |||||
| REF 17 | Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34. | |||||
| REF 18 | Loss 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. | |||||
| REF 19 | vestigial suppressor genes and resistance to aminopterin in Drosophila melanogaster. Heredity. 1992 Nov;69 ( Pt 5):473-7. | |||||
| REF 20 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 21 | Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. Bioorg Med Chem. 2010 Apr 15;18(8):2849-63. | |||||
| REF 22 | New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii. J Med Chem. 1995 Nov 24;38(24):4739-59. | |||||
| REF 23 | 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 c... Bioorg Med Chem. 2010 Feb 15;18(4):1684-701. | |||||
| REF 24 | 2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dih... J Med Chem. 1995 Mar 3;38(5):745-52. | |||||
| REF 25 | Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal m... J Med Chem. 2008 Feb 14;51(3):449-69. | |||||
| REF 26 | X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of ... J Med Chem. 2001 Aug 30;44(18):2928-32. | |||||
| REF 27 | Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three ... J Med Chem. 2003 Apr 24;46(9):1726-36. | |||||
| REF 28 | Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model. J Med Chem. 2003 Jul 31;46(16):3455-62. | |||||
| REF 29 | Nonclassical 2,4-diamino-8-deazafolate analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma gon... J Med Chem. 1996 Apr 26;39(9):1836-45. | |||||
| REF 30 | High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines w... J Med Chem. 1996 Feb 16;39(4):892-903. | |||||
| REF 31 | Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneum... J Med Chem. 1997 Sep 12;40(19):3032-9. | |||||
| REF 32 | Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin. J Med Chem. 1988 Jan;31(1):181-5. | |||||
| REF 33 | CoMFA and CoMSIA analyses of Pneumocystis carinii dihydrofolate reductase, Toxoplasma gondii dihydrofolate reductase, and rat liver dihydrofolate r... J Med Chem. 2005 Mar 10;48(5):1448-69. | |||||
| REF 34 | Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98. | |||||
| REF 35 | Inhibition 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. | |||||
| REF 36 | Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. J Med Chem. 2001 Jun 7;44(12):1993-2003. | |||||
| REF 37 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
| REF 38 | Structure and activity of human mitochondrial peptide deformylase, a novel cancer target. J Mol Biol. 2009 Apr 17;387(5):1211-28. | |||||
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