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(1H-indol-5-yl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone
0.015 mM, 74% inhibition
(4-(9H-fluoren-9-yl) piperazin-1-yl)-(4-methylbenzyl)-methanone
0.015 mM, 99% inhibition
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2,5-difluorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2-fluorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (3-fluorophenyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-Fluoren-9-yl)piperazin-1-yl) (3-tolyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-chlorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-fluorophenyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-methoxyphenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-tolyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (phenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl)(indolin-5-yl)methanone
i.e. Genz10850
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(1H-indole-5-carbonyl)-methanone
0.015 mM, 84% inhibition
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(4-methylbenzyl)-methanone
0.015 mM, 83% inhibition
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-benzyl-methanone
0.015 mM, 81% inhibition
(4-benzylpiperidin-1-yl)(4-methylphenyl)methanone
-
(4-benzylpiperidin-1-yl)(p-tolyl)methanone
-
(4-methylphenyl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone
0.015 mM, 77% inhibition
1-(2-furoyl)-4-[3-(2-ethylphenoxy)benzyl]piperazine
-
39.5% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-(2-methylphenoxy)benzyl]piperazine
-
41.2% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-(phenoxy)benzyl]piperazine
-
KES4, potent inhibitor, 68% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-[2-(sec-butyl)phenoxy]benzyl]piperazine
-
48.8% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-[2-(tert-butyl)phenoxy]benzyl]piperazine
-
66.5% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-[3-(tert-butyl)phenoxy]benzyl]piperazine
-
63.9% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-[3-(trifluoromethyl)phenoxy]benzyl]piperazine
-
45.4% residual activity at 0.05 mM
-
1-(2-furoyl)-4-[3-[4-(methoxycarbonylmethyl)phenoxy]benzyl]piperazine
-
83.4% residual activity at 0.05 mM
-
1-cyclohexyl-N-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide
-
1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide
-
1-cyclohexyl-N-(5'-hydroxy-[1,1':4',1''-terphenyl]-2'-yl)-5-oxopyrrolidine-3-carboxamide
-
2-(2-bromophenoxy)-5-hexylphenol
-
2-(2-chloro-4-fluorophenyl)-N-(4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)phenyl)acetamide
-
2-(2-chlorophenoxy)-5-hexylphenol
-
2-(2-chlorophenoxy)-5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]phenol
-
2-(2-fluorophenoxy)-5-hexylphenol
-
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
-
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
-
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
-
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
-
2-(2-methylphenoxy)-5-[[4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl]phenol
-
2-(4-hexyl-2-hydroxyphenoxy)benzonitrile
-
2-(4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
-
2-(4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
-
2-(4-[[4-(2-bromoethyl)-1H-1,2,3-triazol-1-yl]methyl]-2-hydroxyphenoxy)benzonitrile
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
-
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
-
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
-
2-(ethanesulfonyl)-6-[2-[(E)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol
-
2-(ethanesulfonyl)-7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol
diazaborine, in vitro bactericidal activity against replicating bacteria active against several drug-resistant clinical isolates. AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. It shows good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibits dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection. AN12855 is a promising candidate for the development of new antitubercular agents
2-(o-tolyloxy)-5-hexylphenol
i.e. PT70, slow, tight binding inhibitor. It binds preferentially to the enzyme/NAD+x01complex and has a residence time of 24 min on the target, which is 14000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 A crystal structure of the ternary complex between InhA, NAD+, and PT70 reveals the molecular details of enzyme inhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket
2-[2-hydroxy-4-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]phenoxy]benzonitrile
-
2-[4-[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
-
2-[4-[(4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
-
2-[4-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
-
2-[4-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
-
4-(trifluoromethyl)-2-(4,5-dihydro-4-(2,4-dinitrophenyl)pyrazol-1-yl)pyrimidine
i.e. Genz8575
4-[[1-hydroxy-2-(methanesulfonyl)-1,2-dihydro-2,3,1-benzodiazaborinin-7-yl]oxy]benzonitrile
-
5-butyl-2-phenoxyphenol
-
5-ethyl-2-phenoxyphenol
-
5-hexyl-2-(2-methylphenoxy)phenol
-
5-hexyl-2-phenoxyphenol
-
5-octyl-2-phenoxyphenol
-
5-pentyl-2-phenoxyphenol
-
5-tetradecyl-2-phenoxyphenol
-
5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol
-
5-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol
-
5-[2-[(E)-(hydroxyimino)methyl]phenoxy]-2,1-benzoxaborol-1(3H)-ol
-
5-[[4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl]methyl]-2-(2-methylphenoxy)phenol
-
6-[4-(trifluoromethyl)phenoxy]-2,1-benzoxaborol-1(3H)-ol
-
7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2-(methanesulfonyl)-2,3,1-benzodiazaborinin-1(2H)-ol
-
9H-fluoren-9-yl-piperazine
-
-
-
isoniazid-coenzyme adduct
-
inhibition by several types of isoniazid-coenzyme adducts coexisting in solution is discussed in relation with the structure of the coenzyme, the stereochemistry of the adducts, and their existence as both open and cyclic forms
-
isoniazid-NADP
competitive
N-((4-bromo-1-ethyl-1H-pyrazol-5-yl)methyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
-
N-(2,3-dichlorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-aminophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-bromobenzyl)-4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzamide
-
N-(2-chloro-4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(2-chloro-4-fluorobenzyl)-4-((4-methylthiazol-2-yl)methyl)-benzamide
-
N-(2-chloro-5-(2-phenylacetamido)benzyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
-
N-(2-chloro-5-(3-phenylureido)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(2-chloro-5-aminobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(2-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(2-nitrobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(2-nitrophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-trifluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-benzamide
-
N-(3-bromobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(3-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(3-fluorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(3-methanesulfonybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)benzamide
-
N-(3-propan-2-yloxybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(4-fluoro-2-(trifluoromethyl)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(5-nitrothiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(6-nitrobenzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(benzo[d]thiazol-2-yl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(benzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(benzo[d]thiazol-2-yl)-2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
-
N-(furan-2-yl-methyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
-
N-(furan-2-ylmethyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
-
N-([1,1'-biphenyl]-4-yl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide
-
N-[(1-[[3-hydroxy-4-(2-methylphenoxy)phenyl]methyl]-1H-1,2,3-triazol-4-yl)methyl]cyclopropanecarboxamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(3-methyl-1H-pyrazol-1-yl)methyl]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)-oxy]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)methyl]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)sulfanyl]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(dimethyl-1,3-thiazol-2-yl)methyl]benzamide
-
N-[(2-chloro-4-fluorophenyl)methyl]-4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzamide
-
N-[(4-fluorophenyl)methyl]-4-[[2-methyl-5-(2,2,2-trifluoroethyl)furan-3-yl]methyl]benzamide
-
NAD+
linear competitive inhibitor versus NADH
pentacyano(isoniazid)ferrate(II)
the inorganic complex inhibits both wild-type and isoniazid-resistant Ile21Val mutants of InhA and this inactivation did not require activation by KatG. Molecular dynamics simulations show that the interaction of pentacyano(isoniazid)ferrate(II) with InhA leads to macromolecular instabilities reflected in the long time necessary for simulation convergence. These instabilities are mainly due to perturbation of the substrate binding loop, particularly the partial denaturation of helices alpha6 and alpha7
prothionamide
the prodrug requires activation by EthA, a flavin-dependent monooxygenase. According to the crystal structure of InhA with bound prothionamide-NAD adduct, the propyl-isonicotinic-acyl moiety is located in a hydrophobic pocket formed by the rearrangement of the side chain of Phe149, and an aromatic ringstacking interaction with the pyridine ring
Trp-Tyr-Trp
structure-based computer modelling approach to design a tripeptide inhibitor. Docking studies indicate that the designed peptide has potency 100 times higher than the best known inhibitor. The results suggest that the designed inhibitor is a suitable lead compound for the development of novel anti-TB drugs
[4-(9H-fluoren-9-yl) piperazin-1-yl]-benzyl-methanone
0.015 mM, 97% inhibition
[4-(9H-fluoren-9-yl)piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 94% inhibition
[4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 67% inhibition
[4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](4-methylphenyl)methanone
0.015 mM, 74% inhibition
[4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 81% inhibition
[4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](phenyl)methanone
0.015 mM, 81% inhibition
Ethionamide
the indirect inhibitor forms a covalent adduct with the cofactor
Ethionamide
the prodrug requires activation by EthA, a flavin-dependent monooxygenase. According to the crystal structure of InhA with bound ethionamide-NAD adduct, the ethyl-isonicotinic-acyl moiety is located in a hydrophobic pocket formed by the rearrangement of the side chain of Phe149, and an aromatic ringstacking interaction with the pyridine ring
isoniazid
-
isoniazid
-
fast and efficient inhibition of InhA in the presence of NADH and INH using MnIII-pyrophosphate as nonenzymatic reagent. This chemical oxidant might be a useful tool for further mechanistic studies of isoniazid activation in attempts to establish the exact structures of isoniazid reactive species and InhA inhibitor complex(es).
isoniazid
the indirect inhibitor forms a covalent adduct with the cofactor, leading compound for antitubercular drug therapy
isoniazid
a pro-drug, which is oxidatively activated in vivo by the katG-encoded mycobacterial catalase peroxidase to generate an isonicotinoyl radical. This highly reactive species then reacts nonenzymatically with the cellular pyridine nucleotide coenzymes, NAD+ and NADP+, to generate 12 isonicotinoyl-NAD(P)+ adducts. Of these, the acyclic 4S isomer of isoniazid-NAD+ and the acyclic 4R isomer of isoniazid-NADP+ inhibit the inhA-encoded enoyl-ACP reductase
isoniazid
inhibits through the formation of an INH-NAD adduct which is a slow-onset inhibitor of InhA
isoniazid
prodrug which is biologically activated by the Mycobacterium tuberculosis catalase-peroxidase KatG enzyme. The activation reaction promotes the formation of an isonicotinyl-NAD adduct which inhibits the InhA enzyme, resulting in reduction of mycolic acid biosynthesis
isoniazid
-
acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis
isoniazid
as a pro-drug, isoniazid requires activation by KatG, a catalase-peroxidase enzyme with dual activities of catalase and peroxidase oxidizing isoniazid to an acyl radical binding to position 4 of nicotinamide adenine dinucleotide (NAD) to form an active isoniazid-NAD adduct. Addition of the isonicotinoyl radical to position 4 of the nicotinamide ring can result in two stereoisomersi n which only 4(S) isomers of isoniazid-NAD adduct possess potent activity
isoniazid
inhibits InhA via formation of a covalent adduct with NAD+. KatG, the mycobacterial catalase-peroxidase, is essential for isoniazid activation. While cross-linking studies indicate that enzyme inhibition causes dissociation of the InhA tetramer into dimers, analytical ultracentrifugation and size exclusion chromatography reveal that ligand binding causes a conformational change in the protein that prevents cross-linking across one of the dimer-dimer interfaces in the InhA tetramer
triclosan
-
demonstration of triclosan inhibition of InhA in yeast represents a meaningful variation in studying this effect in mycobacteria, because it occurrs without the potentially confusing aspects of perturbing protein-protein interactions which are presumed vital to mycobacterial FASII, inactivating other important enzymes or eliciting a dedicated transcriptional response in Mycobacterium tuberculosis
triclosan
uncompetitive inhibitor
additional information
-
SAR studies on novel inhibitor scaffolds. Inhibitor scaffolds include the diaryl ethers, pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles, arylamides, fatty acids, and imidazopiperidines, all of which form ternary complexes with InhA and the NAD cofactor, as well as isoniazid and the diazaborines which covalently modify the cofactor. Analysis of the structural data has enabled the development of a common binding mode for the ternary complex inhibitors, which includes a hydrogen bond network, a large hydrophobic pocket and a third size-limited binding area comprised of both polar and non-polar groups. A critical factor in InhA inhibition involves ordering of the substrate binding loop, located close to the active site, and a direct link is proposed between loop ordering and slow onset enzyme inhibition. Slow onset inhibitors have long residence times on the enzyme target, a property that is of critical importance for in vivo activity
-
additional information
overview of 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors
-
additional information
-
overview of 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors
-
additional information
twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives are synthesized and evaluated for their in vitro Mycobacterium tuberculosis InhA inhibition. Compounds are evaluated for their in vitro activity against drug sensitive and resistant Mycobacterium tuberculosis strains and cytotoxicity against RAW 264.7 cell line. Compounds are docked at the active site of InhA to understand their binding mode and differential scanning fluorimetry is performed to ascertain their protein interaction and stability
-
additional information
a series of piperazine derivatives is synthesized and screened as MtInhA inhibitors, which results in the identification of compounds with IC50 values in the submicromolar range
-
additional information
-
the heterologous enzyme is ectopically expressed in a yeast mutant strain from which the native gene encoding the corresponding mitochondrial FASII enzyme is missing.Using an appropriate fungal mitochondrial leader sequence, the mycobacterial protein is directed to the mitochondria, where it can rescue the respiratory growth phenotype of the mutant. The rationale behind the assay is that added antimycolates are foreseen to inhibit the mycobacterial enzyme, thereby recreating the respiratory deficiency of the original mutant, discernible as poor colony formation and growth on glycerol medium
-
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0.0004
(4-(9H-fluoren-9-yl) piperazin-1-yl)-(4-methylbenzyl)-methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.00157
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2,5-difluorophenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.000361
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2-fluorophenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.00024
(4-(9H-fluoren-9-yl)piperazin-1-yl) (3-fluorophenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.00025
(4-(9H-Fluoren-9-yl)piperazin-1-yl) (3-tolyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.00169
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-chlorophenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.000397
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-fluorophenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.0029
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-methoxyphenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.000222
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-tolyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.000183
(4-(9H-fluoren-9-yl)piperazin-1-yl) (phenyl)methanone
Mycobacterium tuberculosis
pH 7.0, 25°C
0.00104
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(1H-indole-5-carbonyl)-methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.00189
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(4-methylbenzyl)-methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.00204
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-benzyl-methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.00516
(4-benzylpiperidin-1-yl)(p-tolyl)methanone
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.0034
1-(2-furoyl)-4-[3-(2-ethylphenoxy)benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.0078
1-(2-furoyl)-4-[3-(2-methylphenoxy)benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.0096
1-(2-furoyl)-4-[3-(phenoxy)benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.0022
1-(2-furoyl)-4-[3-[2-(sec-butyl)phenoxy]benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.005
1-(2-furoyl)-4-[3-[2-(tert-butyl)phenoxy]benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.0018
1-(2-furoyl)-4-[3-[3-(tert-butyl)phenoxy]benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.0228
1-(2-furoyl)-4-[3-[3-(trifluoromethyl)phenoxy]benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
26.8
1-(2-furoyl)-4-[3-[4-(methoxycarbonylmethyl)phenoxy]benzyl]piperazine
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
-
0.00001005
1-cyclohexyl-N-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.00039
1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.00014
1-cyclohexyl-N-(5'-hydroxy-[1,1':4',1''-terphenyl]-2'-yl)-5-oxopyrrolidine-3-carboxamide
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.00004
2-(2-chloro-4-fluorophenyl)-N-(4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)phenyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00616
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00601
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00892
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00716
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00452
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00676
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00312
2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00456
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00312
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00712
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00778
2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.0023
2-(ethanesulfonyl)-6-[2-[(E)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol
Mycobacterium tuberculosis
pH 6.8, 23°C
0.00003
2-(ethanesulfonyl)-7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol
Mycobacterium tuberculosis
pH 6.8, 23°C
0.0000053 - 0.0000503
2-(o-tolyloxy)-5-hexylphenol
0.079
4-[[1-hydroxy-2-(methanesulfonyl)-1,2-dihydro-2,3,1-benzodiazaborinin-7-yl]oxy]benzonitrile
Mycobacterium tuberculosis
pH 6.8, 23°C
0.012
5-[2-[(E)-(hydroxyimino)methyl]phenoxy]-2,1-benzoxaborol-1(3H)-ol
Mycobacterium tuberculosis
pH 6.8, 23°C
0.044
6-[4-(trifluoromethyl)phenoxy]-2,1-benzoxaborol-1(3H)-ol
Mycobacterium tuberculosis
pH 6.8, 23°C
0.0004
7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2-(methanesulfonyl)-2,3,1-benzodiazaborinin-1(2H)-ol
Mycobacterium tuberculosis
pH 6.8, 23°C
0.00016
Genz10850
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.0024
GENZ8575
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.0054
isoniazid
Mycobacterium tuberculosis
-
at pH 6.8 and 25°C
0.00009
N-((4-bromo-1-ethyl-1H-pyrazol-5-yl)methyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00054
N-(2-bromobenzyl)-4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.0005
N-(2-chloro-4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00006
N-(2-chloro-4-fluorobenzyl)-4-((4-methylthiazol-2-yl)methyl)-benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00008
N-(2-chloro-5-(2-phenylacetamido)benzyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00009
N-(2-chloro-5-(3-phenylureido)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00906
N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00816
N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00035
N-(2-chloro-5-aminobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00126
N-(2-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00251
N-(2-nitrobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.001
N-(2-trifluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00158
N-(3-bromobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00158
N-(3-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00251
N-(3-methanesulfonybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00158
N-(3-propan-2-yloxybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00025
N-(4-fluoro-2-(trifluoromethyl)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.0031
N-(4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00512
N-(6-nitrobenzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00836
N-(benzo[d]thiazol-2-yl)-2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00593
N-(benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00686
N-(furan-2-ylmethyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00039
N-([1,1'-biphenyl]-4-yl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide
Mycobacterium tuberculosis
pH and temperature not specified in the publication
0.00009 - 0.00325
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
0.0005
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(3-methyl-1H-pyrazol-1-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.0034
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)-oxy]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00005
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00006
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)sulfanyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.0014
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(dimethyl-1,3-thiazol-2-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00032
N-[(2-chloro-4-fluorophenyl)methyl]-4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00012
N-[(4-fluorophenyl)methyl]-4-[[2-methyl-5-(2,2,2-trifluoroethyl)furan-3-yl]methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00009
[4-(9H-fluoren-9-yl) piperazin-1-yl]-benzyl-methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.0002
[4-(9H-fluoren-9-yl)piperazin-1-yl](1H-indol-5-yl)methanone
Mycobacterium tuberculosis
23°C, pH not specified in the publication
0.0000053
2-(o-tolyloxy)-5-hexylphenol
Mycobacterium tuberculosis
pH 6.8, 23°C, at 10 nM enzyme concentration
0.0000503
2-(o-tolyloxy)-5-hexylphenol
Mycobacterium tuberculosis
pH 6.8, 23°C, at 100 nM enzyme concentration
0.00009
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00025
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
0.00325
N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
Mycobacterium tuberculosis
pH 6.8, 25°C
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malfunction
thermal inactivation of InhA at 42°C in Mycobacterium smegmatis results in the inhibition of mycolic acid biosynthesis, a decrease in hexadecanoic acid (C16:0) and a concomitant increase of tetracosanoic acid (C24:0) in a manner equivalent to that seen in isoniazid-treated cells. The InhA-inactivated cells, like isoniazid-treated cells, undergo a drastic morphological change, leading to cell lysis. InhA inactivation, alone, is sufficient to induce the accumulation of saturated fatty acids, cell wall alterations, and cell lysis
malfunction
-
thermal inactivation of InhA at 42°C in Mycobacterium smegmatis results in the inhibition of mycolic acid biosynthesis, a decrease in hexadecanoic acid (C16:0) and a concomitant increase of tetracosanoic acid (C24:0) in a manner equivalent to that seen in isoniazid-treated cells. The InhA-inactivated cells, like isoniazid-treated cells, undergo a drastic morphological change, leading to cell lysis. InhA inactivation, alone, is sufficient to induce the accumulation of saturated fatty acids, cell wall alterations, and cell lysis
-
metabolism
-
InhA belongs to the FAS-II system and participates in the mycolic acid pathway. The long-chain fatty acids produced by the FAS-II system serve as precursors for the formation of the meromycolic acids, which represent the C40-C60 main chain of mycolic acids
metabolism
key enzyme in the biosynthesis of mycolic acids
metabolism
-
key enzyme involved in the biosynthesis of long-chain fatty acids and of mycolic acids, specific components of the mycobacterial cell wall
metabolism
the enzyjme is a member of an FAS-II system that prefers longer chain fatty acylsubstrates for the purpose of synthesizing mycolic acids, a major component of mycobacterial cell walls
metabolism
the enzyme catalyzes the NADH-dependent reduction of long-chain trans-2-enoyl-ACP fatty acids, an intermediate in mycolic acid biosynthesis
metabolism
the enzyme is a member of the mycobacterial type II dissociated fatty acid biosynthesis system
metabolism
the enzyme is an essential enzyme of the mycolic acid biosynthetic pathway
metabolism
the enzyme is involved in mycolic acid biosynthesis
metabolism
-
the enzyme is involved in mycolic acid biosynthesis. It is part of the dissociative type 2 fatty acid synthase (FASII) system
metabolism
the enzyme is involved in the biosynthesis of mycolic acids
metabolism
the enzyme is involved in the mycobacterial fatty acid biosynthesis pathway. It is essential for the survival of Mycobacterium tuberculosis
metabolism
the enzyme is involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis
metabolism
the enzyme is involved in type II fatty acid biosynthetic pathway
metabolism
-
the enzyme is involved on the biosynthetic pathway for mycolic acids
metabolism
-
InhA belongs to the FAS-II system and participates in the mycolic acid pathway. The long-chain fatty acids produced by the FAS-II system serve as precursors for the formation of the meromycolic acids, which represent the C40-C60 main chain of mycolic acids
-
metabolism
-
the enzyme is involved in type II fatty acid biosynthetic pathway
-
metabolism
-
the enzyme is involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis
-
metabolism
-
the enzyme catalyzes the NADH-dependent reduction of long-chain trans-2-enoyl-ACP fatty acids, an intermediate in mycolic acid biosynthesis
-
metabolism
-
key enzyme in the biosynthesis of mycolic acids
-
metabolism
-
the enzyme is a member of the mycobacterial type II dissociated fatty acid biosynthesis system
-
metabolism
-
the enzyme is involved in the biosynthesis of mycolic acids
-
metabolism
-
the enzyme is an essential enzyme of the mycolic acid biosynthetic pathway
-
metabolism
-
the enzyme is involved in the mycobacterial fatty acid biosynthesis pathway. It is essential for the survival of Mycobacterium tuberculosis
-
metabolism
-
the enzyjme is a member of an FAS-II system that prefers longer chain fatty acylsubstrates for the purpose of synthesizing mycolic acids, a major component of mycobacterial cell walls
-
metabolism
-
the enzyme is involved in mycolic acid biosynthesis
-
physiological function
the enzyme is the causative agent of tuberculosis
physiological function
-
the enzyme is the causative agent of tuberculosis
-
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D148G
diazaborine-resistant mutant
E219A
diazaborine-resistant mutant
E219G
diazaborine-resistant mutant
I202T
diazaborine-resistant mutant
I47T
similar to wild-type InhA, cross-linking of the isoniazid resistant mutant gives three bands on SDS-PAGE assigned to monomer, dimer, and tetrameric forms of the protein. The inhibition of the enzyme with the isoniazid-NAD adduct results in loss of the band assigned to tetramer. In contrast, cross-linking in the presence of saturating concentrations of NADH yields a lower amount of the tetramer upon SDS-PAGE
K165A
mutation prevents NADH from binding
K165M
mutation prevents NADH from binding
K165Q
mutation has no effect on NADH binding
K165R
mutation has no effect on NADH binding
P151S
diazaborine-resistant mutant
R195L
diazaborine-resistant mutant
R195Q
diazaborine-resistant mutant
T266A
phosphoablative mutant with activity similar to wild-type enzyme
T266D
phosphomimetic mutant with strongly reduced activity (31.4% compared to wild-type enzyme), introduction of inhA_T266D fails to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment
T266E
phosphomimetic mutant with strongly reduced activity (29.5% compared to wild-type enzyme), introduction of inhA_T266E fails to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment
Y158A
mutation improves the KM for the cofactor by a factor of 13
Y158F
mutation improves the KM for the cofactor by a factor of 33
Y158S
mutation has no effect on NADH binding
I16T
-
mutation in the glycine-rich loop. Although very flexible, in the wild-type enzyme/NADH complex, the NADH molecule keeps its extended conformation firmly bound to the binding site of the enzyme. In the mutant complex, the NADH pyrophosphate moiety undergoes considerable conformational changes, reducing its interactions with its binding site and probably indicating the initial phase of ligand expulsion from the cavity
-
I47T
-
similar to wild-type InhA, cross-linking of the isoniazid resistant mutant gives three bands on SDS-PAGE assigned to monomer, dimer, and tetrameric forms of the protein. The inhibition of the enzyme with the isoniazid-NAD adduct results in loss of the band assigned to tetramer. In contrast, cross-linking in the presence of saturating concentrations of NADH yields a lower amount of the tetramer upon SDS-PAGE
-
K165A
-
mutation prevents NADH from binding
-
K165Q
-
mutation has no effect on NADH binding
-
S94A
-
mutation confers resistance to both isoniazid and ethionamide. Binding of NADH to the mutant is altered
-
T266A
-
phosphoablative mutant with activity similar to wild-type enzyme
-
T266D
-
phosphomimetic mutant with strongly reduced activity (31.4% compared to wild-type enzyme), introduction of inhA_T266D fails to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment
-
Y158A
-
mutation improves the KM for the cofactor by a factor of 13
-
Y158F
-
mutation improves the KM for the cofactor by a factor of 33
-
Y158S
-
mutation has no effect on NADH binding
-
I16T
diazaborine-resistant mutant
I16T
mutation in the glycine-rich loop. Although very flexible, in the wild-type enzyme/NADH complex, the NADH molecule keeps its extended conformation firmly bound to the binding site of the enzyme. In the mutant complex, the NADH pyrophosphate moiety undergoes considerable conformational changes, reducing its interactions with its binding site and probably indicating the initial phase of ligand expulsion from the cavity
I21V
isoniazid-resistant mutant
I21V
mutation in the glycine-rich loop. Although very flexible, in the wild-type enzyme/NADH complex, the NADH molecule keeps its extended conformation firmly bound to the binding site of the enzyme. In the mutant complex, the NADH pyrophosphate moiety undergoes considerable conformational changes, reducing its interactions with its binding site and probably indicating the initial phase of ligand expulsion from the cavity
I21V
similar to wild-type InhA, cross-linking of the isoniazid resistant mutant gives three bands on SDS-PAGE assigned to monomer, dimer, and tetrameric forms of the protein. The inhibition of the enzyme with the isoniazid-NAD adduct results in loss of the band assigned to tetramer. In contrast, cross-linking in the presence of saturating concentrations of NADH yields a lower amount of the tetramer upon SDS-PAGE
S94A
mutation confers resistance to both isoniazid and ethionamide. Binding of NADH to the mutant is altered
S94A
similar to wild-type InhA, cross-linking of the isoniazid resistant mutant gives three bands on SDS-PAGE assigned to monomer, dimer, and tetrameric forms of the protein. The inhibition of the enzyme with the isoniazid-NAD adduct results in loss of the band assigned to tetramer. In contrast, cross-linking in the presence of saturating concentrations of NADH yields a lower amount of the tetramer upon SDS-PAGE
I21V
-
mutation in the glycine-rich loop. Although very flexible, in the wild-type enzyme/NADH complex, the NADH molecule keeps its extended conformation firmly bound to the binding site of the enzyme. In the mutant complex, the NADH pyrophosphate moiety undergoes considerable conformational changes, reducing its interactions with its binding site and probably indicating the initial phase of ligand expulsion from the cavity
-
I21V
-
isoniazid-resistant mutant
-
I21V
-
similar to wild-type InhA, cross-linking of the isoniazid resistant mutant gives three bands on SDS-PAGE assigned to monomer, dimer, and tetrameric forms of the protein. The inhibition of the enzyme with the isoniazid-NAD adduct results in loss of the band assigned to tetramer. In contrast, cross-linking in the presence of saturating concentrations of NADH yields a lower amount of the tetramer upon SDS-PAGE
-
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Nguyen, M.; Quemard, A.; Broussy, S.; Bernadou, J.; Meunier, B.
Mn(III) pyrophosphate as an efficient tool for studying the mode of action of isoniazid on the InhA protein of Mycobacterium tuberculosis
Antimicrob. Agents Chemother.
46
2137-2144
2002
Mycobacterium tuberculosis
brenda
Quemard, A.; Sacchettini, J.; Dessen, A.; Vilcheze, C.; Bittman, R.; Jacobs, W.J.; Blanchard, J.
Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis
Biochemistry
34
8235-8241
1995
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Joshi, S.; Dixit, S.; Basha, J.; Kulkarni, V.; Aminabhavi, T.; Nadagouda, M.; Lherbet, C.
Pharmacophore mapping, molecular docking, chemical synthesis of some novel pyrrolyl benzamide derivatives and evaluation of their inhibitory activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis
Bioorg. Chem.
81
440-453
2018
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis H37Rv (P9WGR1)
brenda
He, X.; Alian, A.; Ortiz de Montellano, P.
Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides
Bioorg. Med. Chem.
15
6649-6658
2007
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Schroeder, E.; Basso, L.; Santos, D.; De Souza, O.
Molecular dynamics simulation studies of the wild-type, I21V, and I16T mutants of isoniazid-resistant Mycobacterium tuberculosis enoyl reductase (InhA) in complex with NADH Toward the understanding of NADH-InhA different affinities
Biophys. J.
89
876-884
2005
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Subba Rao, G.; Vijayakrishnan, R.; Kumar, M.
Structure-based design of a novel class of potent inhibitors of InhA, the enoyl acyl carrier protein reductase from Mycobacterium tuberculosis A computer modelling approach
Chem. Biol. Drug Des.
72
444-449
2008
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Nguyen, M.; Quemard, A.; Marrakchi, H.; Bernadou, J.; Meunier, B.
The nonenzymatic activation of isoniazid by MnIII-pyrophosphate in the presence of NADH produces the inhibition of the enoyl-ACP reductase InhA from Mycobacterium tuberculosis
Chemistry
4
35-40
2001
Mycobacterium tuberculosis
-
brenda
Guardia, A.; Gulten, G.; Fernandez, R.; Gomez, J.; Wang, F.; Convery, M.; Blanco, D.; Martinez, M.; Perez-Herran, E.; Alonso, M.; Ortega, F.; Rullas, J.; Calvo, D.; Mata, L.; Young, R.; Sacchettini, J.; Mendoza-Losana, A.; Remuinan, M.
N-Benzyl-4-((heteroaryl)methyl)benzamides a new class of direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors with antitubercular activity
ChemMedChem
11
687-701
2016
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Pan, P.; Tonge, P.
Targeting InhA, the FASII enoyl-ACP reductase SAR studies on novel inhibitor scaffolds
Curr. Top. Med. Chem.
12
672-693
2012
Mycobacterium tuberculosis
brenda
Chollet, A.; Maveyraud, L.; Lherbet, C.; Bernardes-Genisson, V.
An overview on crystal structures of InhA protein Apo-form, in complex with its natural ligands and inhibitors
Eur. J. Med. Chem.
146
318-343
2018
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Pedgaonkar, G.; Sridevi, J.; Jeankumar, V.; Saxena, S.; Devi, P.; Renuka, J.; Yogeeswari, P.; Sriram, D.
Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis
Eur. J. Med. Chem.
86
613-627
2014
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Rotta, M.; Pissinate, K.; Villela, A.; Back, D.; Timmers, L.; Bachega, J.; De Souza, O.; Santos, D.; Basso, L.; Machado, P.
Piperazine derivatives Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies
Eur. J. Med. Chem.
90
436-447
2015
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Argyrou, A.; Vetting, M.; Blanchard, J.
New insight into the mechanism of action of and resistance to isoniazid Interaction of Mycobacterium tuberculosis enoyl-ACP reductase with INH-NADP
J. Am. Chem. Soc.
129
9582-9583
2007
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Spagnuolo, L.; Eltschkner, S.; Yu, W.; Daryaee, F.; Davoodi, S.; Knudson, S.; Allen, E.; Merino, J.; Pschibul, A.; Moree, B.; Thivalapill, N.; Truglio, J.; Salafsky, J.; Slayden, R.; Kisker, C.; Tonge, P.
Evaluating the contribution of transition-state destabilization to changes in the residence time of triazole-based InhA inhibitors
J. Am. Chem. Soc.
139
3417-3429
2017
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Vilcheze, C.; Morbidoni, H.; Weisbrod, T.; Iwamoto, H.; Kuo, M.; Sacchettini, J.; Jacobs Jr., W.
Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis
J. Bacteriol.
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4059-4067
2000
Mycolicibacterium smegmatis (P42829), Mycolicibacterium smegmatis mc(2)155 (P42829)
brenda
Rozwarski, D.; Vilcheze, C.; Sugantino, M.; Bittman, R.; Sacchettini, J.
Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate
J. Biol. Chem.
274
15582-15598
1999
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Luckner, S.; Liu, N.; Am Ende, C.; Tonge, P.; Kisker, C.
A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis
J. Biol. Chem.
285
14330-14337
2010
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Vasconcelos, I.; Basso, L.; Santos, D.
Kinetic and equilibrium mechanisms of substrate binding to Mycobacterium tuberculosis enoyl reductase Implications to function-based antitubercular agent design
J. Braz. Chem. Soc.
21
1503-1508
2010
Mycobacterium tuberculosis
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brenda
Da Costa, A.; Pauli, I.; Dorn, M.; Schroeder, E.; Zhan, C.; De Souza, O.
Conformational changes in 2-trans-enoyl-ACP (CoA) reductase (InhA) from M. tuberculosis induced by an inorganic complex A molecular dynamics simulation study
J. Mol. Model.
18
1779-1790
2012
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Gurvitz, A.
Triclosan inhibition of mycobacterial InhA in Saccharomyces cerevisiae Yeast mitochondria as a novel platform for in vivo antimycolate assays
Lett. Appl. Microbiol.
50
399-405
2010
Mycobacterium tuberculosis
brenda
Xia, Y.; Zhou, Y.; Carter, D.; McNeil, M.; Choi, W.; Halladay, J.; Berry, P.; Mao, W.; Hernandez, V.; O'Malley, T.; Korkegian, A.; Sunde, B.; Flint, L.; Woolhiser, L.; Scherman, M.; Gruppo, V.; Hastings, C.; Robertson, G.; Ioerger, T.; Sacchettini, J.
Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
Life Sci. Alliance
1
e201800025
2018
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Marrakchi, H.; Laneelle, G.; Quemard, A.
InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II
Microbiology
146
289-296
2000
Mycobacterium tuberculosis, Mycobacterium tuberculosis mc(2)155
brenda
Lu, X.; You, Q.; Chen, Y.
Recent progress in the identification and development of InhA direct inhibitors of mycobacterium tuberculosis
Mini Rev. Med. Chem.
10
182-193
2010
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Molle, V.; Gulten, G.; Vilcheze, C.; Veyron-Churlet, R.; Zanella-Cleon, I.; Sacchettini, J.; Jacobs Jr, W.; Kremer, L.
Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis
Mol. Microbiol.
78
1591-1605
2010
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Kruh, N.; Rawat, R.; Ruzsicska, B.; Tonge, P.
Probing mechanisms of resistance to the tuberculosis drug isoniazid Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis
Protein Sci.
16
1617-1627
2007
Mycobacterium tuberculosis (P9WGR1), Mycobacterium tuberculosis ATCC 25618 (P9WGR1)
brenda
Jain, S.; Sharma, S.; Sen, D.; Pandya, S.
Enoyl-acyl carrier protein reductase (INHA) A remarkable target to exterminate tuberculosis
Anti-Infect. Agents
19
252-266
2021
Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv
-
brenda
Taira, J.; Umei, T.; Inoue, K.; Kitamura, M.; Berenger, F.; Sacchettini, J.C.; Sakamoto, H.; Aoki, S.
Improvement of the novel inhibitor for Mycobacterium enoyl-acyl carrier protein reductase (InhA) a structure-activity relationship study of KES4 assisted by in silico structure-based drug screening
J. Antibiot.
73
372-381
2020
Mycobacterium tuberculosis
brenda