Target Information
| Target General Information | Top | |||||
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| Target ID |
T79068
(Former ID: TTDS00384)
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| Target Name |
Bacterial Fatty acid synthetase I (Bact inhA)
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| Synonyms |
Enoyl-[acyl-carrier-protein] reductase [NADH]; Bacterial InhA
Click to Show/Hide
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| Gene Name |
Bact inhA
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | HIV-infected patients with tuberculosis [ICD-11: 1B10-1B14] | |||||
| 2 | Mycobacterium infection [ICD-11: 1B10-1B21] | |||||
| Function |
Involved in the resistance against the antituberculosis drugs isoniazid and ethionamide.
Click to Show/Hide
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| BioChemical Class |
CH-CH donor oxidoreductase
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| UniProt ID | ||||||
| Sequence |
MTGLLDGKRILVSGIITDSSIAFHIARVAQEQGAQLVLTGFDRLRLIQRITDRLPAKAPL
LELDVQNEEHLASLAGRVTEAIGAGNKLDGVVHSIGFMPQTGMGINPFFDAPYADVSKGI HISAYSYASMAKALLPIMNPGGSIVGMDFDPSRAMPAYNWMTVAKSALESVNRFVAREAG KYGVRSNLVAAGPIRTLAMSAIVGGALGEEAGAQIQLLEEGWDQRAPIGWNMKDATPVAK TVCALLSDWLPATTGDIIYADGGAHTQLL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Ethionamide | Drug Info | Approved | Tuberculosis | [2], [3] | |
| 2 | Isoniazid | Drug Info | Approved | Tuberculosis | [3] | |
| 3 | Prothionamide | Drug Info | Approved | Tuberculosis | [4] | |
| 4 | Pyrazinamide | Drug Info | Approved | Mycobacterium infection | [2], [3], [5] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | AFN-1720 | Drug Info | Phase 2 | Bacterial infection | [6] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | MMV00/0053 | Drug Info | Terminated | Malaria | [7] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 49 Inhibitor drugs | + | ||||
| 1 | Ethionamide | Drug Info | [4], [8] | |||
| 2 | Isoniazid | Drug Info | [1], [9], [10] | |||
| 3 | Prothionamide | Drug Info | [4], [11] | |||
| 4 | Pyrazinamide | Drug Info | [12] | |||
| 5 | AFN-1720 | Drug Info | [13] | |||
| 6 | MMV00/0053 | Drug Info | [14] | |||
| 7 | (4-benzylpiperidin-1-yl)(2-fluorophenyl)methanone | Drug Info | [15] | |||
| 8 | (4-benzylpiperidin-1-yl)(3-chlorophenyl)methanone | Drug Info | [15] | |||
| 9 | (4-benzylpiperidin-1-yl)(m-tolyl)methanone | Drug Info | [15] | |||
| 10 | (4-benzylpiperidin-1-yl)(p-tolyl)methanone | Drug Info | [16], [15] | |||
| 11 | (4-phenylpiperazin-1-yl)(p-tolyl)methanone | Drug Info | [15] | |||
| 12 | 2-(2-aminophenoxy)-5-hexylphenol | Drug Info | [17] | |||
| 13 | 2-(3-aminophenoxy)-5-hexylphenol | Drug Info | [17] | |||
| 14 | 2-(4,6-dimethoxypyrimidin-2-yloxy)-5-hexylphenol | Drug Info | [17] | |||
| 15 | 2-(4-aminophenoxy)-5-hexylphenol | Drug Info | [17] | |||
| 16 | 2-(4-hexyl-2-methoxyphenoxy)pyrimidine | Drug Info | [17] | |||
| 17 | 2-bromo-4-methylphenyl 2-nitrobenzoate | Drug Info | [18] | |||
| 18 | 2-Hexadecynoic acid | Drug Info | [19] | |||
| 19 | 2-nitro-N-(2,4,5-trichlorophenyl)benzamide | Drug Info | [18] | |||
| 20 | 4-(2-Thienyl)-1-(4-Methylbenzyl)-1h-Imidazole | Drug Info | [20] | |||
| 21 | 4-chloro-N-(2,5-dichlorophenyl)-3-nitrobenzamide | Drug Info | [18] | |||
| 22 | 5-hexyl-2-(2-nitrophenoxy)phenol | Drug Info | [17] | |||
| 23 | 5-hexyl-2-(3-nitrophenoxy)phenol | Drug Info | [17] | |||
| 24 | 5-hexyl-2-(4-nitrophenoxy)phenol | Drug Info | [17] | |||
| 25 | 5-hexyl-2-(pyrazin-2-yloxy)phenol | Drug Info | [17] | |||
| 26 | 5-hexyl-2-(pyridin-2-yloxy)phenol | Drug Info | [17] | |||
| 27 | 5-hexyl-2-(pyridin-3-yloxy)phenol | Drug Info | [17] | |||
| 28 | 5-hexyl-2-(pyridin-4-yloxy)phenol | Drug Info | [17] | |||
| 29 | 5-hexyl-2-(pyrimidin-2-yloxy)phenol | Drug Info | [17] | |||
| 30 | 5-hexyl-2-phenoxyphenol | Drug Info | [17] | |||
| 31 | 5-octyl-2-phenoxyphenol | Drug Info | [21] | |||
| 32 | 5-PENTYL-2-PHENOXYPHENOL | Drug Info | [16] | |||
| 33 | Beta-D-Glucose | Drug Info | [20] | |||
| 34 | C16-Fatty-Acyl-Substrate-Mimic | Drug Info | [20] | |||
| 35 | Diclosan | Drug Info | [20] | |||
| 36 | Genz-10850 | Drug Info | [20] | |||
| 37 | Indole Naphthyridinone | Drug Info | [20] | |||
| 38 | N-(2,4-dichlorophenyl)-2-nitrobenzamide | Drug Info | [18] | |||
| 39 | N-(2,4-dichlorophenyl)-4-methyl-3-nitrobenzamide | Drug Info | [18] | |||
| 40 | N-(2,4-dimethylphenyl)-2-nitrobenzamide | Drug Info | [18] | |||
| 41 | N-(2,5-dichlorophenyl)-4-methoxy-3-nitrobenzamide | Drug Info | [18] | |||
| 42 | N-(2-(4-hexyl-2-hydroxyphenoxy)phenyl)acetamide | Drug Info | [17] | |||
| 43 | N-(3,5-dichlorophenyl)-2-nitrobenzamide | Drug Info | [18] | |||
| 44 | N-(3,5-dichlorophenyl)-4-methoxy-3-nitrobenzamide | Drug Info | [18] | |||
| 45 | N-(3,5-dimethoxyphenyl)-4-methyl-2-nitrobenzamide | Drug Info | [18] | |||
| 46 | N-(3-(4-hexyl-2-hydroxyphenoxy)phenyl)acetamide | Drug Info | [17] | |||
| 47 | N-(4-(4-hexyl-2-hydroxyphenoxy)phenyl)acetamide | Drug Info | [17] | |||
| 48 | N-(4-(diethylamino)phenyl)-2-nitrobenzamide | Drug Info | [18] | |||
| 49 | Nicotinamide-Adenine-Dinucleotide | Drug Info | [20] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: NADH | Ligand Info | |||||
| Structure Description | Mycobacterium tuberculosis InhA-S94A mutant in complex with NADH | PDB:4DTI | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [22] |
| PDB Sequence |
GLLDGKRILV
12 SGIITDSSIA22 FHIARVAQEQ32 GAQLVLTGFD42 RLRLIQRITD52 RLPAKAPLLE 62 LDVQNEEHLA72 SLAGRVTEAI82 GAGNKLDGVV92 HAIGFMPQTG102 MGINPFFDAP 112 YADVSKGIHI122 SAYSYASMAK132 ALLPIMNPGG142 SIVGMDFDPS152 RAMPAYNWMT 162 VAKSALESVN172 RFVAREAGKY182 GVRSNLVAAG192 PIRTLAMSAI202 VGGALGEEAG 212 AQIQLLEEGW222 DQRAPIGWNM232 KDATPVAKTV242 CALLSDWLPA252 TTGDIIYADG 262 GAHTQLL
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GLY14
2.767
ILE15
3.548
ILE16
3.329
THR17
4.941
SER19
4.982
SER20
2.632
ILE21
2.948
ALA22
4.500
PHE41
3.380
LEU63
3.154
ASP64
3.046
VAL65
3.073
GLN66
4.318
ALA94
3.373
ILE95
3.182
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Triclosan | Ligand Info | |||||
| Structure Description | Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) inhibited by triclosan | PDB:2B35 | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [23] |
| PDB Sequence |
TGLLDGKRIL
11 VSGIITDSSI21 AFHIARVAQE31 QGAQLVLTGF41 DRLRLIQRIT51 DRLPAKAPLL 61 ELDVQNEEHL71 ASLAGRVTEA81 IGAGNKLDGV91 VHSIGFMPQT101 GMGINPFFDA 111 PYADVSKGIH121 ISAYSYASMA131 KALLPIMNPG141 GSIVGMDFDP151 SRAMPAYNWM 161 TVAKSALESV171 NRFVAREAGK181 YGVRSNLVAA191 GPIRTGAQIQ216 LLEEGWDQRA 226 PIGWNMKDAT236 PVAKTVCALL246 SDWLPATTGD256 IIYADGGAHT266 QLL |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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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 | |||||
|---|---|---|---|---|---|---|
| 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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| Drug Resistance Mutation (DRM) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Diversity in enoyl-acyl carrier protein reductases. Cell Mol Life Sci. 2009 May;66(9):1507-17. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8. | |||||
| REF 4 | Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007 Jan 22;204(1):73-8. | |||||
| REF 5 | 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: 7287). | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038764) | |||||
| REF 7 | Annual report of Medicines for Malaria Venture in 2002. | |||||
| REF 8 | Calcium-activated conductance in skate electroreceptors: current clamp experiments. J Gen Physiol. 1977 Feb;69(2):121-43. | |||||
| REF 9 | Enoyl reductases as targets for the development of anti-tubercular and anti-malarial agents. Curr Drug Targets. 2007 Mar;8(3):399-411. | |||||
| REF 10 | Screening for novel antituberculosis agents that are effective against multidrug resistant tuberculosis. Curr Top Med Chem. 2007;7(5):499-507. | |||||
| REF 11 | Ability of the Ca2+ ionophores A23187 and ionomycin to mimic some of the effects of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production, ornithine decarboxylase activity, and DNA synthesis in mouse epidermis in vivo. Cancer Res. 1990 Sep 15;50(18):5806-12. | |||||
| REF 12 | Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. 2000 Sep;6(9):1043-7. | |||||
| REF 13 | Affinium Pharmaceuticals Announces the Initiation of a Phase 1 Intravenous Clinical Trial of a New Antibiotic Prodrug, and the Closing of a Follow-on Financing Round. PR Newswire Sep. 4, 2013 10:16 PM. | |||||
| REF 14 | SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase. IUBMB Life. 2010 Mar;62(3):204-13. | |||||
| REF 15 | Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg Med Chem. 2007 Nov 1;15(21):6649-58. | |||||
| REF 16 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 17 | Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. Bioorg Med Chem Lett. 2008 May 15;18(10):3029-33. | |||||
| REF 18 | Discovery of potential new InhA direct inhibitors based on pharmacophore and 3D-QSAR analysis followed by in silico screening. Eur J Med Chem. 2009 Sep;44(9):3718-30. | |||||
| REF 19 | 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections. Bioorg Med Chem. 2010 Nov 1;18(21):7475-85. | |||||
| REF 20 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 21 | Natural products, small molecules, and genetics in tuberculosis drug development. J Med Chem. 2008 May 8;51(9):2606-12. | |||||
| REF 22 | Towards a new tuberculosis drug: pyridomycin - nature's isoniazid. EMBO Mol Med. 2012 Oct;4(10):1032-42. | |||||
| REF 23 | Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) inhibited by triclosan | |||||
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