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Literature summary for 2.7.11.12 extracted from

  • Baker, D.A.; Stewart, L.B.; Large, J.M.; Bowyer, P.W.; Ansell, K.H.; Jimenez-Diaz, M.B.; El Bakkouri, M.; Birchall, K.; Dechering, K.J.; Bouloc, N.S.; Coombs, P.J.; Whalley, D.; Harding, D.J.; Smiljanic-Hurley, E.; Wheldon, M.C.; Walker, E.M.; Dessens, J.T.; Lafuente, M.J.; Sanz, L.M.; Gamo, F.J.; Ferrer, S.B.; , H.
    A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission (2017), Nat. Commun., 8, 430 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
expressed in Escherichia coli Rosetta 2(DE3) pLysS cells Plasmodium berghei
expressed in Escherichia coli Rosetta 2(DE3) pLysS cells Plasmodium chabaudi
expressed in Escherichia coli Rosetta 2(DE3) pLysS cells Plasmodium vivax
expressed in Escherichia coli Rosetta 2(DE3) pLysS cells Plasmodium falciparum

Crystallization (Commentary)

Crystallization (Comment) Organism
enzyme in complex with inhibitor ML1, hanging drop vapor diffusion method, using 10% (w/v) PEG 5000 MME, 5% (w/v) tacsimate, 0.1M HEPES pH 7.0, 1 5mM spermidine, and 25% (v/v) glycerol. Enzyme in complex with inhibitor ML10, hanging drop vapor diffusion method, using 15.5% (w/v) PEG 3350, 0.1M HEPES pH 7, 0.1 M succinate pH 7.0 Plasmodium vivax

Protein Variants

Protein Variants Comment Organism
T618Q the mutant exhibits a reduced sensitivity to many inhibitors of between 500 and more than 100000fold as compared to the wild type enzyme Plasmodium falciparum

Inhibitors

Inhibitors Comment Organism Structure
4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium berghei
4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium chabaudi
4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium falciparum
4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium vivax
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium berghei
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium chabaudi
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium falciparum
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium vivax
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium berghei
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium chabaudi
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium falciparum
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
-
Plasmodium vivax
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
-
Plasmodium berghei
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
-
Plasmodium chabaudi
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
-
Plasmodium falciparum
4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
-
Plasmodium vivax
4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium berghei
4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium chabaudi
4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium falciparum
4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium vivax
N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
-
Plasmodium berghei
N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
-
Plasmodium chabaudi
N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
-
Plasmodium falciparum
N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
-
Plasmodium vivax
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium berghei
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium chabaudi
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium falciparum
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium vivax
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium berghei
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium chabaudi
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium falciparum
N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
-
Plasmodium vivax
N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium berghei
N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium chabaudi
N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium falciparum
N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
-
Plasmodium vivax
N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide most potent inhibitor Plasmodium berghei
N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide most potent inhibitor Plasmodium chabaudi
N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide most potent inhibitor Plasmodium falciparum
N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide most potent inhibitor Plasmodium vivax

Organism

Organism UniProt Comment Textmining
Plasmodium berghei
-
-
-
Plasmodium chabaudi
-
-
-
Plasmodium falciparum Q8I719
-
-
Plasmodium vivax A5K0N4
-
-
Plasmodium vivax Salvador A5K0N4
-
-

Purification (Commentary)

Purification (Comment) Organism
HiTrap TALON (cobalt) column chromatography Plasmodium berghei
HiTrap TALON (cobalt) column chromatography Plasmodium chabaudi
HiTrap TALON (cobalt) column chromatography Plasmodium vivax
HiTrap TALON (cobalt) column chromatography Plasmodium falciparum

Source Tissue

Source Tissue Comment Organism Textmining
gametocyte
-
Plasmodium berghei
-
gametocyte
-
Plasmodium chabaudi
-
gametocyte
-
Plasmodium vivax
-
gametocyte
-
Plasmodium falciparum
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + FAM-GRTGRRNSI-NH2
-
Plasmodium berghei ADP + phosphorylated FAM-GRTGRRNSI-NH2
-
?
ATP + FAM-GRTGRRNSI-NH2
-
Plasmodium chabaudi ADP + phosphorylated FAM-GRTGRRNSI-NH2
-
?
ATP + FAM-GRTGRRNSI-NH2
-
Plasmodium vivax ADP + phosphorylated FAM-GRTGRRNSI-NH2
-
?
ATP + FAM-GRTGRRNSI-NH2
-
Plasmodium falciparum ADP + phosphorylated FAM-GRTGRRNSI-NH2
-
?
ATP + FAM-GRTGRRNSI-NH2
-
Plasmodium vivax Salvador ADP + phosphorylated FAM-GRTGRRNSI-NH2
-
?

Synonyms

Synonyms Comment Organism
cyclic GMP-dependent protein kinase
-
Plasmodium berghei
cyclic GMP-dependent protein kinase
-
Plasmodium chabaudi
cyclic GMP-dependent protein kinase
-
Plasmodium vivax
cyclic GMP-dependent protein kinase
-
Plasmodium falciparum
PKG
-
Plasmodium berghei
PKG
-
Plasmodium chabaudi
PKG
-
Plasmodium vivax
PKG
-
Plasmodium falciparum

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00000013
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
0.00000016
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide
0.00000045
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.00000079
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.00000079
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
0.00000088
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
0.00000119
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
0.00000171
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum 4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.0000031
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
0.00000434
-
wild type enzyme, at pH 7.4 and 25°C Plasmodium falciparum N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
0.000231
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.000842
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.001713
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum 4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(piperazin-1-yl)phenyl]pyrimidin-2-amine
0.0084
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-yl]pyrimidin-2-amine
0.02954
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum N-[5-(3-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl)-2-fluorophenyl]methanesulfonamide
0.0525
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum N-(cyclopropylmethyl)-4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
0.0737
-
mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide
0.1
-
IC50 above 0.1 mM, mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum 4-[7-[(dimethylamino)methyl]-2-[3-(methanesulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine
0.1
-
IC50 above 0.1 mM, mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum N-(3-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]phenyl)methanesulfonamide
0.1
-
IC50 above 0.1 mM, mutant enzyme T618Q, at pH 7.4 and 25°C Plasmodium falciparum N-(5-[3-(2-aminopyrimidin-4-yl)-7-[(dimethylamino)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl]-2-fluorophenyl)methanesulfonamide