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(1E)-1-[4-[(3,5-dichloropyridin-4-yl)oxy]phenyl]ethanone thiosemicarbazone
-
-
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-benzylpyrazinediium)
-
minimal inhibitory concentration: 0.003536 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-methylpyrazinediium)
-
minimal inhibitory concentration: 0.002418 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-phenylpyrazinediium)
-
minimal inhibitory concentration: 0.018 mM
1-(4-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
-
1-[3-(3,4-dichlorophenoxy)propyloxy]-5-isopropylbiguanide
-
i.e. PS-16
1-[3-(4-chlorophenoxy)propyloxy]-5-isopropylbiguanide
-
i.e. PS-33
2,2'-({6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}diimino)diethanol
-
minimal inhibitory concentration: 0.149 mM
2,3-bis(hydrazino)quinoxaline
-
-
2-[[(4-[[(2-amino-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]phenyl)carbonyl]amino]hexanedioic acid
-
-
2-[[1-(3-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl]-N-prop-2-en-1-ylhydrazinecarbothioamide
-
-
3-[[(4-chlorophenyl)sulfonyl]methyl]-N'-hydroxybenzenecarboximidamide
-
-
4,6-di(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-N-(4-nitrophenyl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.020 mM
4,6-di(morpholin-4-yl)-N-(4-nitrophenyl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.0258 mM
4-(benzyloxy)benzaldehyde thiosemicarbazone
-
-
4-chloro-N-[4-(hydroxycarbamimidoyl)benzyl]benzamide
-
-
4-[(3,5-dichloropyridin-4-yl)oxy]-N'-hydroxybenzenecarboximidamide
-
-
4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy]benzaldehyde thiosemicarbazone
-
-
5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
-
5-(3-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
-
5-(4-bromophenyl)-6-ethylpyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-isobutylpyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-isopropylpyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine
-
-
5-(4-chlorophenyl)-6-propylpyrimidine-2,4-diamine
-
-
6-ethyl-5-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
-
6-[[(2,5-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(3,4-dimethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
benzaldehyde semicarbazone
-
-
methyl 4-(2,6-diamino-5-phenylpyrimidin-4-yl)butanoate
-
-
methyl 4-[2,6-diamino-5-(3-chlorophenyl)pyrimidin-4-yl]butanoate
-
-
methyl 5-[(1E)-N-carbamoylethanehydrazonoyl]-2,3'-bithiophene-5'-carboxylate
-
-
N-(4-nitrophenyl)-4,6-di(piperidin-1-yl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.130 mM
N-(4-nitrophenyl)-4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.140 mM
N2,N2,N4,N4-tetraethyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.027 mM
N2,N4-bis(3-fluorophenyl)-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.022968 mM
N2,N4-bis[2-(morpholin-4-yl)ethyl]-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0042 mM
N2,N4-bis[3-(1H-imidazol-1-yl)propyl]-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0021 mM
N2,N4-bis[3-(morpholin-4-yl)propyl]-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0039 mM
N2,N4-di-tert-butyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.139 mM
N2,N4-dibenzyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.023393 mM
N2,N4-dibutyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0055 mM
N2,N4-dicycloheptyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0041 mM
N2,N4-dicyclohexyl-N6-(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.0024 mM
N2-(4-nitrophenyl)-N4,N6-dioctyl-1,3,5-triazine-2,4,6-triamine
-
minimal inhibitory concentration: 0.021 mM
NCI0086195
-
docking analysis, overview
NCI0109835
-
docking analysis, overview
NCI0156252
-
docking analysis, overview
NCI0164641
-
docking analysis, overview
NCI0211175
-
docking analysis, overview
NCI0289533
-
docking analysis, overview
NCI0289541
-
docking analysis, overview
NCI0309401
-
docking analysis, overview
NCI0369769
-
docking analysis, overview
NCI0696662
-
docking analysis, overview
triclosan
-
specifically targets both wild-type and pyrimethamine-resistant Plasmodium falciparum dihydrofolate reductases and selectively inhibits both the wild-type and pyrimethamine-resistant enzymes compared to human DHFR
pyrimethamine
-
pyrimethamine
CoMFA and quantum chemical calculations studies on pyrimethamine derivatives active against quadruple mutant N5I/C59R/S108N/I164L. Residue N108 is the cause of pyrimethamine resistance with the highest repusive interaction energy
6-[[(2,5-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-[[(2,5-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
identified from docking studies
cycloguanil
-
-
cycloguanil
-
wild-type and several Ser108 mutant enzymes
cycloguanil
-
an antifolate enzyme inhibitor used in treatment of malaria
cycloguanil
-
and prodrug proguanil
pyrimethamine
-
-
pyrimethamine
-
wild-type and several mutants of Ser108
pyrimethamine
-
study on Plasmodium falciparum isolates from 118 children in Cote d'Ivoire. 39.5% are highly resistant to pyrimethamine, with IC50 values above 2000 nM. 39% of the isolates have mutant dihydrofolate reductase and 94% mutant dihydropteroate synthetase genes, and mutant dihydrofolate reducatase is assovciated with resistance to pyrimethamine in vivo and in vitro
pyrimethamine
-
an antifolate enzyme inhibitor used in treatment of malaria
WR99210
-
-
WR99210
-
and PS-15 W99210 prodrug. Active site binding structure of wild-type enzyme, and mutants C59R/S108N and A16V/N51I/C59R/S108N, overview
WR99210
-
docking analysis, overview
additional information
-
in presence of up to 4 M urea, wild-type retains more than 80% of its catalytic activity. Mutant W48Y loses more than 20% of activity in presence of 1 M urea
-
additional information
-
design and development of enzyme inhibitors based on on the bioactive conformation of WR99210 extracted from the X-ray crystal structure of quadruple mutant parasite DHFR enzyme, virtual screening and molecular docking, overview
-
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0.0042 - 0.0086
7,8-dihydrofolate
0.005 - 0.05
7,8-dihydrofolate
0.0042
7,8-dihydrofolate
wild-type, pH 5.0, 25°C
0.0049
7,8-dihydrofolate
mutant Y35G/F37L, pH 5.0, 25°C
0.0053
7,8-dihydrofolate
mutant K27E, pH 5.0, 25°C
0.0055
7,8-dihydrofolate
mutant Y35L/F37R, pH 5.0, 25°C
0.0076
7,8-dihydrofolate
mutant Y35Q/F37R, pH 5.0, 25°C
0.0086
7,8-dihydrofolate
mutant Y35L/F37T, pH 5.0, 25°C
0.0043
NADPH
mutant Y35G/F37L, pH 5.0, 25°C
0.0048
NADPH
mutant Y35L/F37T, pH 5.0, 25°C
0.0058
NADPH
wild-type, pH 5.0, 25°C
0.0068
NADPH
mutant K27E, pH 5.0, 25°C
0.0097
NADPH
mutant Y35L/F37R, pH 5.0, 25°C
0.0105
NADPH
mutant Y35Q/F37R, pH 5.0, 25°C
0.005
7,8-dihydrofolate
-
mutant N51I/C59R/N108T/I164L, pH 7.0
0.0051
7,8-dihydrofolate
-
wild-type, 25°C, pH 7.0
0.0052
7,8-dihydrofolate
-
mutant N51I/C59R/N108S/I164L, pH 7.0
0.0081
7,8-dihydrofolate
-
mutant N51I/C59R/S108N/I164L/K96N, pH 7.0
0.0083
7,8-dihydrofolate
-
mutant I51N/C59R/N108S/I164L, pH 7.0
0.013
7,8-dihydrofolate
-
recombinant wild-type enzyme
0.0133
7,8-dihydrofolate
-
mutant N51I/C59R/S108N/I164L, pH 7.0
0.014
7,8-dihydrofolate
-
recombinant mutants S108T and S108A
0.0145
7,8-dihydrofolate
-
mutant N51I/C59R/S108N/I164L/D187A, pH 7.0
0.01465
7,8-dihydrofolate
-
mutant N51I/C59R/S108N/I164L/I150V/N182I/N201D, pH 7.0
0.02 - 0.025
7,8-dihydrofolate
-
recombinant mutants S108G, S108N and S108C
0.0207
7,8-dihydrofolate
-
mutant N51I/C59R/S108N/I164L , pH 8.0, 25°C
0.0209
7,8-dihydrofolate
-
mutant N51I/C59R/S108N, pH 8.0, 25°C
0.0231
7,8-dihydrofolate
-
mutant W48Y, 25°C, pH 7.0
0.0324
7,8-dihydrofolate
-
mutant W48Y/N188Y, 25°C, pH 7.0
0.0444
7,8-dihydrofolate
-
wild-type, pH 8.0, 25°C
0.05
7,8-dihydrofolate
-
recombinant mutant S108Q
0.0027
NADPH
-
wild-type, 25°C, pH 7.0
0.00345
NADPH
-
mutant W48Y/N188Y, 25°C, pH 7.0
0.0045
NADPH
-
mutant W48Y, 25°C, pH 7.0
0.005
NADPH
-
recombinant wild-type enzyme
0.00595
NADPH
-
mutant N51I/C59R/N108T/I164L, pH 7.0
0.00643
NADPH
-
mutant N51I/C59R/S108N/I164L, pH 7.0
0.0065
NADPH
-
mutant N51I/C59R/S108N/I164L/D187A, pH 7.0
0.007
NADPH
-
recombinant mutant S108N
0.0072
NADPH
-
mutant N51I/C59R/S108N/I164L/K96N, pH 7.0
0.009
NADPH
-
recombinant mutants S108G, S108A and S108C
0.0113
NADPH
-
mutant N51I/C59R/S108N/I164L/I150V/N182I/N201D, pH 7.0
0.014
NADPH
-
recombinant mutant S108Q
0.017
NADPH
-
recombinant mutant S108T
0.0232
NADPH
-
wild-type, pH 8.0, 25°C
0.0267
NADPH
-
mutant I51N/C59R/N108S/I164L, pH 7.0
0.0373
NADPH
-
mutant N51I/C59R/S108N/I164L , pH 8.0, 25°C
0.0379
NADPH
-
mutant N51I/C59R/S108N, pH 8.0, 25°C
0.052
NADPH
-
mutant N51I/C59R/N108S/I164L, pH 7.0
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0.00000024 - 0.0000018
cycloguanil
0.00000012 - 0.0000012
pyrimethamine
0.000001 - 0.0000534
5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine
0.0000008 - 0.0000033
5-(3-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
0.0000003 - 0.000303
5-(4-bromophenyl)-6-ethylpyrimidine-2,4-diamine
0.0000043 - 0.001576
5-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine-2,4-diamine
0.0000003 - 0.000385
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
0.0000003 - 0.000798
5-(4-chlorophenyl)-6-isobutylpyrimidine-2,4-diamine
0.0000003 - 0.000541
5-(4-chlorophenyl)-6-isopropylpyrimidine-2,4-diamine
0.0000029 - 0.003461
5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine
0.0000005 - 0.000359
5-(4-chlorophenyl)-6-propylpyrimidine-2,4-diamine
0.0000009 - 0.000617
6-ethyl-5-(4-methoxyphenyl)pyrimidine-2,4-diamine
0.000001 - 0.000158
cycloguanil
0.0000006 - 0.0000241
methyl 4-(2,6-diamino-5-phenylpyrimidin-4-yl)butanoate
0.0000005 - 0.0000028
methyl 4-[2,6-diamino-5-(3-chlorophenyl)pyrimidin-4-yl]butanoate
0.00000072 - 0.000514
pyrimethamine
0.00000044 - 0.0000155
WR99210
0.00000024
cycloguanil
mutant K27E, pH 5.0, 25°C
0.00000028
cycloguanil
mutant Y35G/F37L, pH 5.0, 25°C
0.0000006
cycloguanil
mutant Y35Q/F37R, pH 5.0, 25°C
0.0000012
cycloguanil
mutant Y35L/F37R, pH 5.0, 25°C
0.0000015
cycloguanil
wild-type, pH 5.0, 25°C
0.0000018
cycloguanil
mutant Y35L/F37T, pH 5.0, 25°C
0.00000012
pyrimethamine
mutant K27E, pH 5.0, 25°C
0.0000002
pyrimethamine
mutant Y35G/F37L, pH 5.0, 25°C
0.00000057
pyrimethamine
mutant Y35L/F37T, pH 5.0, 25°C
0.0000006
pyrimethamine
wild-type, pH 5.0, 25°C
0.00000061
pyrimethamine
mutant Y35Q/F37R, pH 5.0, 25°C
0.0000012
pyrimethamine
mutant Y35L/F37R, pH 5.0, 25°C
0.000001
5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0000126
5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.0000534
5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000008
5-(3-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0000014
5-(3-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.0000033
5-(3-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000003
5-(4-bromophenyl)-6-ethylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0000443
5-(4-bromophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000303
5-(4-bromophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000043
5-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.000742
5-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.001576
5-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000003
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0000539
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000385
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000003
5-(4-chlorophenyl)-6-isobutylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.000099
5-(4-chlorophenyl)-6-isobutylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000798
5-(4-chlorophenyl)-6-isobutylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000003
5-(4-chlorophenyl)-6-isopropylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.000113
5-(4-chlorophenyl)-6-isopropylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000541
5-(4-chlorophenyl)-6-isopropylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000029
5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0006
5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.003461
5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000005
5-(4-chlorophenyl)-6-propylpyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.0000494
5-(4-chlorophenyl)-6-propylpyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000359
5-(4-chlorophenyl)-6-propylpyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000009
6-ethyl-5-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
wild-type, pH 7.0, 25°C
0.000086
6-ethyl-5-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
mutant C59R/S108N, pH 7.0, 25°C
0.000617
6-ethyl-5-(4-methoxyphenyl)pyrimidine-2,4-diamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.000001
cycloguanil
-
wild-type, 25°C, pH 7.0
0.0000016
cycloguanil
-
recombinant mutant S108T
0.00000199
cycloguanil
-
mutant W48Y/N188Y, 25°C, pH 7.0
0.000002
cycloguanil
-
recombinant mutant S108A
0.0000026
cycloguanil
-
recombinant wild-type enzyme
0.000003
cycloguanil
-
recombinant mutant S108C
0.00000548
cycloguanil
-
mutant W48Y, 25°C, pH 7.0
0.000015
cycloguanil
-
recombinant mutant S108N
0.000017
cycloguanil
-
recombinant mutant S108G
0.000158
cycloguanil
-
recombinant mutant S108Q
0.0000006
methyl 4-(2,6-diamino-5-phenylpyrimidin-4-yl)butanoate
-
wild-type, pH 7.0, 25°C
0.0000055
methyl 4-(2,6-diamino-5-phenylpyrimidin-4-yl)butanoate
-
mutant C59R/S108N, pH 7.0, 25°C
0.0000241
methyl 4-(2,6-diamino-5-phenylpyrimidin-4-yl)butanoate
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000005
methyl 4-[2,6-diamino-5-(3-chlorophenyl)pyrimidin-4-yl]butanoate
-
wild-type, pH 7.0, 25°C
0.0000027
methyl 4-[2,6-diamino-5-(3-chlorophenyl)pyrimidin-4-yl]butanoate
-
mutant N51I/C59R/S108N/I164L, pH 7.0, 25°C
0.0000028
methyl 4-[2,6-diamino-5-(3-chlorophenyl)pyrimidin-4-yl]butanoate
-
mutant C59R/S108N, pH 7.0, 25°C
0.00000072
pyrimethamine
-
wild-type, 25°C, pH 7.0
0.000001
pyrimethamine
-
mutant W48Y/N188Y, 25°C, pH 7.0
0.0000014
pyrimethamine
-
recombinant mutant S108T
0.0000015
pyrimethamine
-
recombinant wild-type enzyme
0.00000174
pyrimethamine
-
mutant W48Y, 25°C, pH 7.0
0.000004
pyrimethamine
-
recombinant mutant S108A
0.000006
pyrimethamine
-
recombinant mutant S108C
0.000007
pyrimethamine
-
recombinant mutant S108G
0.0000081
pyrimethamine
-
mutant I51N/C59R/N108S/I164L, pH 7.0
0.000013
pyrimethamine
-
recombinant mutant S108N
0.0000176
pyrimethamine
-
mutant N51I/C59R/N108S/I164L, pH 7.0
0.0000724
pyrimethamine
-
mutant N51I/C59R/N108T/I164L, pH 7.0
0.000095
pyrimethamine
-
recombinant mutant S108Q
0.000147
pyrimethamine
-
mutant N51I/C59R/S108N/I164L/I150V/N182I/N201D, pH 7.0
0.000209
pyrimethamine
-
mutant N51I/C59R/S108N/I164L, pH 7.0
0.000292
pyrimethamine
-
mutant N51I/C59R/S108N/I164L/K96N, pH 7.0
0.000514
pyrimethamine
-
mutant N51I/C59R/S108N/I164L/D187A, pH 7.0
0.00000044
WR99210
-
wild-type, 25°C, pH 7.0
0.00000085
WR99210
-
mutant N51I/C59R/S108N/I164L/K96N, pH 7.0
0.0000011
WR99210
-
mutant N51I/C59R/S108N/I164L/I150V/N182I/N201D, pH 7.0
0.0000012
WR99210
-
mutant N51I/C59R/S108N/I164L/D187A, pH 7.0
0.00000121
WR99210
-
mutant W48Y/N188Y, 25°C, pH 7.0
0.00000154
WR99210
-
mutant W48Y, 25°C, pH 7.0
0.0000021
WR99210
-
mutant N51I/C59R/S108N/I164L, pH 7.0
0.0000036
WR99210
-
mutant I51N/C59R/N108S/I164L, pH 7.0
0.0000073
WR99210
-
mutant N51I/C59R/N108S/I164L, pH 7.0
0.0000155
WR99210
-
mutant N51I/C59R/N108T/I164L, pH 7.0
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K27E
kinetic properties similar to wild-type, increase in solubility
N5I/C59R/S108N/I164L
naturally occuring mutant. Residue N108 is the cause of pyrimethamine resistance with the highest repulsive interaction energy
Y35G/F37L
kinetic properties similar to wild-type, increase in solubility
Y35L/F37R
kinetic properties similar to wild-type, increase in solubility
Y35L/F37T
kinetic properties similar to wild-type, increase in solubility
Y35Q/F37R
kinetic properties similar to wild-type, increase in solubility
A16V
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
A16V/N51I/C59R/S108N
-
point mutations of the active site residues lead to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine, binding structure modelling, overview
C59R
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
I164L
-
mutation I164L is not associated with high-level sulfadoxine-pyrimethamine resistance or poor outcome among infected adults living where malaria is highly endemic
I164X
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
I51N/C59R/N108S/I164L
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
N51I
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
N51I/C59R/N108S/I164L
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
N51I/C59R/N108T/I164L
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
N51I/C59R/S108N/I164L/D187A
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
N51I/C59R/S108N/I164L/I150V/N182I/N201D
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
N51I/C59R/S108N/I164L/K96N
-
mutant isolated in an effort to mimic the impact of drug pressure on the selection of dihydrofolate reductase mutations in the malaria parasite population, based on DHFR-TS-QM mutation which exhibits the highest degree of antifolate resistance developed in the field
S108A
-
combinatorial mutagenesis
S108C
-
combinatorial mutagenesis
S108D
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108E
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108F
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108G
-
combinatorial mutagenesis
S108H
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108I
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108L
-
combinatorial mutagenesis, reduced activity
S108M
-
combinatorial mutagenesis, reduced activity
S108N/C59R
-
natural mutants isolated in a study on the association between the clinical and parasitological response to sulfadoxinepyrimethamine and allelic combinations of dihydrofolate reductase and dihydropteroate synthase genes
S108N/N51I
-
natural mutants isolated in a study on the association between the clinical and parasitological response to sulfadoxinepyrimethamine and allelic combinations of dihydrofolate reductase and dihydropteroate synthase genes
S108P
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108Q
-
combinatorial mutagenesis, reduced activity, conferred resistance to pyrimethamine and cycloguanil
S108R
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108V
-
combinatorial mutagenesis, reduced activity
S108W
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
S108Y
-
combinatorial mutagenesis, no detectable activity on refolding from inclusion bodies
W48Y
-
3% of wild-type activity
W48Y/N188Y
-
28.9% of wild-type activity
C59R/S108N
-
mutant with increased resistance to anitfolate antimalarials, use for screening inhibitors
C59R/S108N
-
point mutations of the active site residues lead to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine, binding structure modelling, overview
N51I/C59R/S108N
-
natural mutants isolated in a study on the association between the clinical and parasitological response to sulfadoxinepyrimethamine and allelic combinations of dihydrofolate reductase and dihydropteroate synthase genes. The majority of clinical isolates is characterized as quadruple, i.e. 196 isolates with mutations N51I-C59R-S108N in dihydrofolate reductase and A437G dihydropteroate synthase
N51I/C59R/S108N
-
pyrimethamine-resistant mutant, 50% decrease in Km value
N51I/C59R/S108N/I164L
-
mutant with increased resistance to anitfolate antimalarials, use for screening inhibitors
N51I/C59R/S108N/I164L
-
mutant highly resistant to pyrimethamine, but sensitive to WR99210, i.e. DHFT-QM mutant
N51I/C59R/S108N/I164L
-
pyrimethamine-resistant mutant, 50% decrease in Km value
S108N
-
combinatorial mutagenesis, conferred resistance to pyrimethamine and cycloguanil
S108N
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
S108T
-
combinatorial mutagenesis, reduced activity
S108T
-
point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine
additional information
deletion mutant lacking residues 2-5 of N-terminal tail compared to an analogous deletion of residues 2-22 of the N-terminal tail and construction of a mutant in the crossover helix that interacts with the dihydrofolate reductase active site by substitution of its five residues with alanines to form the Ala-FACE helix mutant. Mutations to the linker region within the bifunctional thymidylate synthase-dihydrofolate reductase affect neither catalytic rate nor domain-domain communication. Deletion of the N-terminal tail, although in a location remote from the active site, decreases the dihydrofolate reductase single rate and the bifunctional thymidylate synthase-dihydrofolate reductase rate by a factor of 2. The 2-fold activation of the dihydrofolate reductase rate by thymidylate synthase ligands remains intact, although even the activated N-terminal mutant has just half the dihydrolfolate reductase activity of the wild-type enzyme. However, the reciprocal communication between thymidlyate synthase active site and dihydrolfolate reductase ligands is impaired in N-terminal mutants
additional information
-
deletion mutant lacking residues 2-5 of N-terminal tail compared to an analogous deletion of residues 2-22 of the N-terminal tail and construction of a mutant in the crossover helix that interacts with the dihydrofolate reductase active site by substitution of its five residues with alanines to form the Ala-FACE helix mutant. Mutations to the linker region within the bifunctional thymidylate synthase-dihydrofolate reductase affect neither catalytic rate nor domain-domain communication. Deletion of the N-terminal tail, although in a location remote from the active site, decreases the dihydrofolate reductase single rate and the bifunctional thymidylate synthase-dihydrofolate reductase rate by a factor of 2. The 2-fold activation of the dihydrofolate reductase rate by thymidylate synthase ligands remains intact, although even the activated N-terminal mutant has just half the dihydrolfolate reductase activity of the wild-type enzyme. However, the reciprocal communication between thymidlyate synthase active site and dihydrolfolate reductase ligands is impaired in N-terminal mutants
additional information
-
sequence analysis of enzyme isolated from strains in different regions of India. Prevalence of double enzyme mutants and some with triple mutants in isolates from mainland, presence of qudruple mutants in isolates from Car Nicobar Island. Association between the degree of malaria transmission and the number of enzyme mutations
additional information
-
construction of 19 mutants of residue W48. All mutants show very low specific activites
additional information
-
heteroduplex tracking assay to detect dihydrofolate redctase L164-mutations in variants representing 1% of the parasites in an individual host
additional information
-
pyrimethamine-resistant quadruple mutant 51I/59R/108N/213A, kcat value 0.68 per s, Km value for dihydrofolate, 0.0102 mM, Km value for NADPH, 0.0309 mM
additional information
-
study on Plasmodium falciparum isolates from 118 children in Cote d'Ivoire. 39.5% are highly resistant to pyrimethamine, with IC50 values above 2000 nM. 39% of the isolates have mutant dihydrofolate reductase and 94% mutant dihydropteroate synthetase genes, and mutant dihydrofolate reductase is associated with resistance to pyrimethamine in vivo and in vitro
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biotechnology
in vivo screening system to select for functionally active proteins with increased solubility. Fusion of enzyme to green fluorescent protein as reporter for solubility
drug development
modeling of 31 pyrimethamine derivatives into the active site of dihydrofolate reductase obtained from crystal structures 1J3I.pdb and 1J3K.pdb. Evaluation of predicted binding modes and key protein-ligand interactions
analysis
-
heteroduplex tracking assay to detect dihydrofolate redctase L164-mutations in variants representing 1% of the parasites in an individual host
biotechnology
-
method for screening combinatorial or other libraries of Plasmodium falciparum enzyme based on affinities of the inhibitors with the enzyme
drug development
-
modeling of 32 pyrimethamine derivatives into the active site of dihydrofolate reductase obtained from crystal structure 1J3K.pdb. Evaluation of predicted binding modes and key protein-ligand interactions
drug development
-
the enzyme is a target for antifolate drugs. The parasite develops resistance to several used antifolates via mutations in the active site, e.g. point mutations of residues Ala16, Ile51, Cys59, Ser108 and Ile164, overview
medicine
-
sequence analysis of enzyme isolated from strains in different regions of India. Prevalence of double enzyme mutants and some with triple mutants in isolates from mainland, presence of qudruple mutants in isolates from Car Nicobar Island. Association between the degree of malaria transmission and the number of enzyme mutations
medicine
-
in a total of 92 Plasmodium falsiparum-infected blood samples from children in Mozambique, the frequency of the sulphadoxine/pyrimethamine resistance-associated dihydrofolate reductase triple mutants 51I/59R/108N and of dihydrofolate reductase /dihydropteroate synthetase quintuple mutants 51I/59R/108N + 437G/540E was 93% and 47%, respectively. However, no dihydrolfolate reductase 164L mutants were detected
medicine
-
in parasites isolated from Sudanese patients treated with sulphadoxine/pyrimethamine or sulphadoxine/pyrimethamine plus chloroquine, mutations have been detected in dihydrofolate reductase at N51I, S108N, and C59R, plus mutations in dihydropteroate synthetase. There is no significant correlation between multiplicity of mutation and response to sulphadoxine/pyrimethamine
medicine
-
study on Plasmodium falciparum isolates from 118 children in Cote d'Ivoire. 39.5% are highly resistant to pyrimethamine, with IC50 values above 2000 nM. 39% of the isolates have mutant dihydrofolate reductase and 94% mutant dihydropteroate synthetase genes, and mutant dihydrofolate reductase is associated with resistance to pyrimethamine in vivo and in vitro
medicine
-
study on prevalence and frequency of dihydrofolate reductase and dihydropteroate synthetase mutations associated with sulfadoxine-pyrimethamine resistance at surveillance sites in Southern Mozambique. Frequency of dihydrofolate triple mutation increased from 0.26 in 1999 to 0.96 in 2003, remaining high in 2004. Parasites with both dihydrofolate reductase triple mutation and dihydropteroate synthetase double mutations had increased in 2001, but decreased by 2004. The peaking of sulfadoxine-pyrimethamine resistance markers in 2001 coincided with a sulfadoxine-pyrimethamine resistant malaria epidemic in neighboring regions
medicine
-
study on the association between the clinical and parasitological response to sulfadoxinepyrimethamine and allelic combinations of dihydrofolate reductase and dihydropteroate synthase genes. Determination of dihydrofolate reductase and dihydropteroate synthase genotypes is of limited value to predict the treatment outcome in individual patients, mostly due to few treatment failures and few wild-type haplotypes. The majority of clinical isolates is characterized as quadruple, i.e. 196 isolates with mutations N51I-C59R-S108N in dihydrofolate reductase and A437G dihydropteroate synthase, or triple mutants, i.e. 97 isolates with mutations N51I-C59R-S108N in dihydrofolate reductase and wild-type dihydropteroate synthase, or S108N + N51I or C59R in dihydrofolate reductase and A437G in dihydropteroate synthase. Wild-type, single mutation, and double mutation were observed in 29, 20, and 13 parasites, respectively
medicine
-
study on the effect of co-trimoxazole prophylaxis on Plasmodium falciparum antifolate resistance development among HIV-infected persons. Mutation I164L is not associated with high-level sulfadoxine-pyrimethamine resistance or poor outcome among adults living where malaria is highly endemic
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18
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103
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78
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51
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Plasmodium falciparum
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Probing the role of parasite-specific, distant structural regions on communication and catalysis in the bifunctional thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum
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47
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Plasmodium falciparum (P13922), Plasmodium falciparum
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22
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24
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Plasmodium falciparum (P13922), Plasmodium falciparum
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In silico screening against wild-type and mutant Plasmodium falciparum dihydrofolate reductase
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26
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Plasmodium falciparum (P13922), Plasmodium falciparum
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6
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Dihydrofolate reductase I164L mutations in Plasmodium falciparum isolates: clinical outcome of 14 Kenyan adults infected with parasites harbouring the I164L mutation
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102
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Modelling and informatics in the analysis of P. falciparum DHFR enzyme inhibitors
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15
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Quantitative Structure Activity Relationship Study of 2,4,6-Trisubstituted-s-triazine Derivatives as Antimalarial Inhibitors of Plasmodium Falciparum Dihydrofolate Reductase
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8
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