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Literature summary for 6.1.1.15 extracted from

  • Hewitt, S.N.; Dranow, D.M.; Horst, B.G.; Abendroth, J.A.; Forte, B.; Hallyburton, I.; Jansen, C.; Baragana, B.; Choi, R.; Rivas, K.L.; Hulverson, M.A.; Dumais, M.; Edwards, T.E.; Lorimer, D.D.; Fairlamb, A.H.; Gray, D.W.; Read, K.D.; Lehane, A.M.; Kirk, K.; Myler, P.J.; Wernimont, A.; Walpole, C.; Stacy, R.; Bar, B.a.r.r.
    Biochemical and Structural characterization of selective allosteric inhibitors of the Plasmodium falciparum drug target, prolyl-tRNA-synthetase (2017), ACS Infect. Dis., 3, 34-44 .
    View publication on PubMedView publication on EuropePMC
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Cloned(Commentary)

Cloned (Comment) Organism
expressed in Escherichia coli BL21-(DE3)R3 Rosetta cells Plasmodium falciparum

Crystallization (Commentary)

Crystallization (Comment) Organism
sitting drop vapor diffusion method, using 10% (w/v) PEG-800, 20% (v/v) ethylene glycol, 0.1 M MES/imidazole, pH 6.5, and 0.03 M each sodium fluoride, sodium bromide, and sodium iodide Plasmodium falciparum

Inhibitors

Inhibitors Comment Organism Structure
2-[4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide
-
 Plasmodium falciparum
3-[4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-1H-pyrazol-3-yl]propanamide
-
 Plasmodium falciparum
4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine
-
 Plasmodium falciparum
4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-1H-pyrazole-3-carboxamide
-
 Plasmodium falciparum
febrifugine
-
 Plasmodium falciparum
glyburide
-
 Plasmodium falciparum
halofuginone
-
 Plasmodium falciparum
N-(2,4-difluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(3-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[1-methyl-3-(trifluoromethyl)-4-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-3-(2-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-[2-(2-hydroxyethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-[2-(hydroxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-(4-fluorophenyl)-N'-[4-[3-(2-hydroxyethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
-
 Plasmodium falciparum
N-([3-[5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methyl)methanesulfonamide
-
 Plasmodium falciparum
N-Boc-halofuginone less than 20% inhibition at 1 mM Plasmodium falciparum
N-[3-(2-cyanoethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
N-[3-(cyanomethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
N-[3-cyano-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
N-[3-[2-(dimethylamino)ethyl]-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
N-[4-(3,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
N-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-methoxyphenyl)urea
-
 Plasmodium falciparum
N-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-[2-(morpholin-4-yl)pyridin-4-yl]urea
-
 Plasmodium falciparum
N-[4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
-
 Plasmodium falciparum
TCMDC-124506 competitive inhibitor Plasmodium falciparum

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + L-proline + tRNAPro Plasmodium falciparum
-
 AMP + diphosphate + L-prolyl-tRNAPro
-
 ?

Organism

Organism UniProt Comment Textmining
Plasmodium falciparum Q8I5R7
-
-

Purification (Commentary)

Purification (Comment) Organism
His Trap column chromatography and Superdex 75 gel filtration Plasmodium falciparum

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + L-proline + tRNAPro
-
 Plasmodium falciparum AMP + diphosphate + L-prolyl-tRNAPro
-
 ?

Synonyms

Synonyms Comment Organism
Prolyl-tRNA synthetase
-
 Plasmodium falciparum
ProRS
-
 Plasmodium falciparum

Cofactor

Cofactor Comment Organism Structure
ATP
-
 Plasmodium falciparum

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0025
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(2,4-difluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.003
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-5-yl]urea
0.004
-
 at pH 7.0 and 37°C Plasmodium falciparum N-[3-[2-(dimethylamino)ethyl]-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.005
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.005
-
 at pH 7.0 and 37°C Plasmodium falciparum N-[3-cyano-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.005
-
 at pH 7.0 and 37°C Plasmodium falciparum TCMDC-124506
0.006
-
 at pH 7.0 and 37°C Plasmodium falciparum N-[3-(cyanomethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.008
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(3-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.008
-
 at pH 7.0 and 37°C Plasmodium falciparum 3-[4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-1H-pyrazol-3-yl]propanamide
0.009
-
 at pH 7.0 and 37°C Plasmodium falciparum N-[3-(2-cyanoethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.013
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-[3-(2-hydroxyethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.014
-
 at pH 7.0 and 37°C Plasmodium falciparum 4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-1H-pyrazole-3-carboxamide
0.018
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-3-(2-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl]urea
0.02
-
 at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-[2-(hydroxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum 4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-[4-(3,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-methoxyphenyl)urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-[2-(morpholin-4-yl)pyridin-4-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-[4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N'-(4-fluorophenyl)urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum 2-[4-(4-fluorophenyl)-5-[[(4-fluorophenyl)carbamoyl]amino]-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[4-[2-(2-hydroxyethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-([3-[5-[[(4-fluorophenyl)carbamoyl]amino]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methyl)methanesulfonamide
0.05
-
 IC50 above 0.05 mM, at pH 7.0 and 37°C Plasmodium falciparum N-(4-fluorophenyl)-N'-[1-methyl-3-(trifluoromethyl)-4-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]urea