Target Information

Target General Information

Top

Target ID

T79068 (Former ID: TTDS00384)

Target Name

Bacterial Fatty acid synthetase I (Bact inhA)

Synonyms

Enoyl-[acyl-carrier-protein] reductase [NADH]; Bacterial InhA

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Gene Name

Bact inhA

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

HIV-infected patients with tuberculosis [ICD-11: 1B10-1B14]

Mycobacterium infection [ICD-11: 1B10-1B21]

Function

Involved in the resistance against the antituberculosis drugs isoniazid and ethionamide.

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BioChemical Class

CH-CH donor oxidoreductase

UniProt ID

INHA_MYCTU

Sequence

MTGLLDGKRILVSGIITDSSIAFHIARVAQEQGAQLVLTGFDRLRLIQRITDRLPAKAPL
LELDVQNEEHLASLAGRVTEAIGAGNKLDGVVHSIGFMPQTGMGINPFFDAPYADVSKGI
HISAYSYASMAKALLPIMNPGGSIVGMDFDPSRAMPAYNWMTVAKSALESVNRFVAREAG
KYGVRSNLVAAGPIRTLAMSAIVGGALGEEAGAQIQLLEEGWDQRAPIGWNMKDATPVAK
TVCALLSDWLPATTGDIIYADGGAHTQLL

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 3 Approved Drugs

Ethionamide

Drug Info

Approved

Tuberculosis

[4], [3]

Isoniazid

Drug Info

Approved

Tuberculosis

[3]

Prothionamide

Drug Info

Approved

Tuberculosis

[5]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

MMV00/0053

Drug Info

Terminated

Malaria

[7]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 43 Inhibitor drugs

Ethionamide

Drug Info

[5], [8]

Isoniazid

Drug Info

[1], [9], [10]

Prothionamide

Drug Info

[5], [11]

MMV00/0053

Drug Info

[12]

(4-benzylpiperidin-1-yl)(2-fluorophenyl)methanone

Drug Info

[13]

(4-benzylpiperidin-1-yl)(m-tolyl)methanone

Drug Info

[13]

(4-benzylpiperidin-1-yl)(p-tolyl)methanone

Drug Info

[14], [13]

(4-phenylpiperazin-1-yl)(p-tolyl)methanone

Drug Info

[13]

2-(2-aminophenoxy)-5-hexylphenol

Drug Info

[15]

2-(3-aminophenoxy)-5-hexylphenol

Drug Info

[15]

2-(4,6-dimethoxypyrimidin-2-yloxy)-5-hexylphenol

Drug Info

[15]

2-(4-aminophenoxy)-5-hexylphenol

Drug Info

[15]

2-(4-hexyl-2-methoxyphenoxy)pyrimidine

Drug Info

[15]

2-bromo-4-methylphenyl 2-nitrobenzoate

Drug Info

[16]

2-Hexadecynoic acid

Drug Info

[17]

2-nitro-N-(2,4,5-trichlorophenyl)benzamide

Drug Info

[16]

4-(2-Thienyl)-1-(4-Methylbenzyl)-1h-Imidazole

Drug Info

[18]

4-chloro-N-(2,5-dichlorophenyl)-3-nitrobenzamide

Drug Info

[16]

5-hexyl-2-(2-nitrophenoxy)phenol

Drug Info

[15]

5-hexyl-2-(3-nitrophenoxy)phenol

Drug Info

[15]

5-hexyl-2-(4-nitrophenoxy)phenol

Drug Info

[15]

5-hexyl-2-(pyrazin-2-yloxy)phenol

Drug Info

[15]

5-hexyl-2-(pyridin-2-yloxy)phenol

Drug Info

[15]

5-hexyl-2-(pyridin-3-yloxy)phenol

Drug Info

[15]

5-hexyl-2-(pyridin-4-yloxy)phenol

Drug Info

[15]

5-hexyl-2-(pyrimidin-2-yloxy)phenol

Drug Info

[15]

5-hexyl-2-phenoxyphenol

Drug Info

[15]

5-octyl-2-phenoxyphenol

Drug Info

[19]

5-PENTYL-2-PHENOXYPHENOL

Drug Info

[14]

Beta-D-Glucose

Drug Info

[18]

C16-Fatty-Acyl-Substrate-Mimic

Drug Info

[18]

Diclosan

Drug Info

[18]

Genz-10850

Drug Info

[18]

N-(2,4-dichlorophenyl)-2-nitrobenzamide

Drug Info

[16]

N-(2,4-dimethylphenyl)-2-nitrobenzamide

Drug Info

[16]

N-(2,5-dichlorophenyl)-4-methoxy-3-nitrobenzamide

Drug Info

[16]

N-(2-(4-hexyl-2-hydroxyphenoxy)phenyl)acetamide

Drug Info

[15]

N-(3,5-dichlorophenyl)-2-nitrobenzamide

Drug Info

[16]

N-(3,5-dichlorophenyl)-4-methoxy-3-nitrobenzamide

Drug Info

[16]

N-(3,5-dimethoxyphenyl)-4-methyl-2-nitrobenzamide

Drug Info

[16]

N-(4-(4-hexyl-2-hydroxyphenoxy)phenyl)acetamide

Drug Info

[15]

N-(4-(diethylamino)phenyl)-2-nitrobenzamide

Drug Info

[16]

Nicotinamide-Adenine-Dinucleotide

Drug Info

[18]

Drug Binding Sites of Target

Top

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

[20]

PDB Sequence

GLLDGKRILV

¹²

SGIITDSSIA

²²

FHIARVAQEQ

³²

GAQLVLTGFD

⁴²

RLRLIQRITD

⁵²

RLPAKAPLLE

⁶²

LDVQNEEHLA

⁷²

SLAGRVTEAI

⁸²

GAGNKLDGVV

⁹²

HAIGFMPQTG

¹⁰²

MGINPFFDAP

¹¹²

YADVSKGIHI

¹²²

SAYSYASMAK

¹³²

ALLPIMNPGG

¹⁴²

SIVGMDFDPS

¹⁵²

RAMPAYNWMT

¹⁶²

VAKSALESVN

¹⁷²

RFVAREAGKY

¹⁸²

GVRSNLVAAG

¹⁹²

PIRTLAMSAI

²⁰²

VGGALGEEAG

²¹²

AQIQLLEEGW

²²²

DQRAPIGWNM

²³²

KDATPVAKTV

²⁴²

CALLSDWLPA

²⁵²

TTGDIIYADG

²⁶²

GAHTQLL

Residue

Distance (Å)

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

Residue

Distance (Å)

GLY96

3.388

PHE97

4.249

ILE122

3.609

MET147

3.226

ASP148

3.179

PHE149

3.619

LYS165

2.864

ALA191

3.663

GLY192

3.582

PRO193

3.288

ILE194

2.691

THR196

3.196

ALA198

4.656

MET199

3.814

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

[21]

PDB Sequence

TGLLDGKRIL

¹¹

VSGIITDSSI

²¹

AFHIARVAQE

³¹

QGAQLVLTGF

⁴¹

DRLRLIQRIT

⁵¹

DRLPAKAPLL

⁶¹

ELDVQNEEHL

⁷¹

ASLAGRVTEA

⁸¹

IGAGNKLDGV

⁹¹

VHSIGFMPQT

¹⁰¹

GMGINPFFDA

¹¹¹

PYADVSKGIH

¹²¹

ISAYSYASMA

¹³¹

KALLPIMNPG

¹⁴¹

GSIVGMDFDP

¹⁵¹

SRAMPAYNWM

¹⁶¹

TVAKSALESV

¹⁷¹

NRFVAREAGK

¹⁸¹

YGVRSNLVAA

¹⁹¹

GPIRTGAQIQ

²¹⁶

LLEEGWDQRA

²²⁶

PIGWNMKDAT

²³⁶

PVAKTVCALL

²⁴⁶

SDWLPATTGD

²⁵⁶

IIYADGGAHT

²⁶⁶

QLL

Residue

Distance (Å)

GLY96

3.235

PHE97

3.450

MET98

2.987

MET103

3.377

PHE149

3.608

Residue

Distance (Å)

TYR158

2.345

MET161

3.537

LYS165

3.832

PRO193

3.861

ILE194

4.997

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
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

Different Human System Profiles of Target

Top

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

There is no similarity protein (E value < 0.005) for this target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

Diversity in enoyl-acyl carrier protein reductases. Cell Mol Life Sci. 2009 May;66(9):1507-17.

REF 2

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 3

Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007 Jan 22;204(1):73-8.

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

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 13

Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg Med Chem. 2007 Nov 1;15(21):6649-58.

REF 14

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 15

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 16

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 17

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 18

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 19

Natural products, small molecules, and genetics in tuberculosis drug development. J Med Chem. 2008 May 8;51(9):2606-12.

REF 20

Towards a new tuberculosis drug: pyridomycin - nature's isoniazid. EMBO Mol Med. 2012 Oct;4(10):1032-42.

REF 21

Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) inhibited by triclosan

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