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Literature summary for 1.5.1.3 extracted from

  • Liu, J.; Bolstad, D.B.; Smith, A.E.; Priestley, N.D.; Wright, D.L.; Anderson, A.C.
    Probing the active site of Candida glabrata dihydrofolate reductase with high resolution crystal structures and the synthesis of new inhibitors (2009), Chem. Biol. Drug Des., 73, 62-74.
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.5.1.3

Application

Application Comment Organism
drug development the essential enzyme is a target for development of specific inhibitors [Candida] glabrata

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant enzyme, hanging drop vapor diffusion method, 13 mg/ml protein in 20 mM Tris pH 8.0, 20% glycerol, 0.1 mM EDTA and 2 mM DTT, incubation with 1.5 mM NADPH, mixing with an equal volume of crystallization solution containing 0.1 M Tris, pH 8.5, 35-40% PEG 4000 and 0.3-0.4 M MgCl2, X-ray diffraction structure determination and analysis at 1.95-2.11 A resolution [Candida] glabrata

Inhibitors

Inhibitors Comment Organism Structure
2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)-3-methylbut-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)-3-methylbut-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)pent-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)pent-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(3,5-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(3,5-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(4-methoxyphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(4-methoxyphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(4-tertbutylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(4-tertbutylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
2,4-diamino-5-[3-(3-methoxy-5-(6-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 [Candida] glabrata
2,4-diamino-5-[3-(3-methoxy-5-(6-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
 Homo sapiens
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
-
 [Candida] glabrata
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
-
 Homo sapiens
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
 [Candida] glabrata
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
 Homo sapiens
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
 [Candida] glabrata
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
 Homo sapiens
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
-
 [Candida] glabrata
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
-
 Homo sapiens
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
-
 [Candida] glabrata
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
-
 Homo sapiens
additional information inhibitor design, structure-activity relationships of the antifolates: methyl groups at the meta and para positions of the distal phenyl ring achieve the greatest number of interactions with the pathogenic enzyme and the greatest degree of selectivity over the human enzyme, antifungal activity can be tuned with substitution patterns at the propargyl and para-phenyl positions, overview [Candida] glabrata

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
7,8-dihydrofolate + NADPH + H+ Homo sapiens
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
7,8-dihydrofolate + NADPH + H+ [Candida] glabrata
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-
[Candida] glabrata Q6FPH0
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrofolate + NADPH + H+
-
 Homo sapiens 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
7,8-dihydrofolate + NADPH + H+
-
 [Candida] glabrata 5,6,7,8-tetrahydrofolate + NADP+
-
 ?

Synonyms

Synonyms Comment Organism
DHFR
-
 Homo sapiens
DHFR
-
 [Candida] glabrata

Cofactor

Cofactor Comment Organism Structure
NADPH
-
 Homo sapiens
NADPH
-
 [Candida] glabrata

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00000055
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.00000061
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(3,5-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0000055
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0000064
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(4-methoxyphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0000073
-
-
 [Candida] glabrata 5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.0000073
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(6-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.00001
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3-methoxy-5-(4-tertbutylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.000011
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)pent-1-ynyl]-6-methylpyrimidine
0.000017
-
-
 [Candida] glabrata 6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
0.000025
-
-
 [Candida] glabrata 6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
0.000027
-
-
 [Candida] glabrata 2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)-3-methylbut-1-ynyl]-6-methylpyrimidine
0.00003
-
-
 [Candida] glabrata 5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.000039
-
-
 [Candida] glabrata 3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
0.00018
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(4-methoxyphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0002
-
-
 Homo sapiens 2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)-3-methylbut-1-ynyl]-6-methylpyrimidine
0.00021
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(4-tertbutylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.00029
-
-
 Homo sapiens 2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)pent-1-ynyl]-6-methylpyrimidine
0.0004
-
-
 Homo sapiens 6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
0.00075
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.00122
-
-
 Homo sapiens 5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.0013
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.00138
-
-
 Homo sapiens 6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
0.0014
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(3,5-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0014
-
-
 Homo sapiens 2,4-diamino-5-[3-(3-methoxy-5-(6-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
0.0017
-
-
 Homo sapiens 5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.00571
-
-
 Homo sapiens 3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol