Literature summary for 1.5.1.3 extracted from

Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D.
Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function (2008), Proteins, 73, 889-901.

Crystallization (Commentary)

Crystallization (Comment)	Organism
structure-based three-dimensional quantitative structure-activity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase. Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands	Homo sapiens
structure-based three-dimensional quantitative structureactivity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase. Crystal structures of complexes of the enzymewith eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands	Trypanosoma cruzi

Crystallization (Comment)

Organism

structure-based three-dimensional quantitative structure-activity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase. Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands

Homo sapiens

structure-based three-dimensional quantitative structureactivity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase. Crystal structures of complexes of the enzymewith eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands

Trypanosoma cruzi

Inhibitors

Inhibitors	Comment	Organism
2-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid	ratio of IC50 values human/Trypanosoma enzyme 47	Homo sapiens
2-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid	ratio of IC50 values human/Trypanosoma enzyme 47	Trypanosoma cruzi
3-((3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenoxy)methyl)benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 86	Homo sapiens
3-((3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenoxy)methyl)benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 86	Trypanosoma cruzi
3-[(3-(3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl)prop-2-yn-1-yl)oxy]benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 77	Homo sapiens
3-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 77	Trypanosoma cruzi
4-((5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl)ethynyl)benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 129	Homo sapiens
4-((5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl)ethynyl)benzoic acid	ratio of IC50 values human/Trypanosoma enzyme is 129	Trypanosoma cruzi
6-[[(2,5-diethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine	-	Homo sapiens
6-[[(2,5-diethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine	-	Trypanosoma cruzi
7-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]hept-6-ynoic acid	ratio of IC50 values human/Trypanosoma enzyme is 49	Homo sapiens
7-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]hept-6-ynoic acid	ratio of IC50 values human/Trypanosoma enzyme is 49	Trypanosoma cruzi
additional information	structure-based three-dimensional quantitative structure-activity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase and comparison with human dihydrofolate reductase. Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands, good agreement between experimental and predicted enzyme inhibition data	Homo sapiens
additional information	structure-based three-dimensional quantitative structure-activity relationship 3D-QSAR approach to predict the biochemical activity for inhibitors of Trypanosoma cruzi dihydrofolate reductase-thymidylate synthase. Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state have been used to validate and refine docking poses of ligands, good agreement between experimental and predicted enzyme inhibition data	Trypanosoma cruzi
trimetrexate	-	Homo sapiens
trimetrexate	-	Trypanosoma cruzi

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P00374	-	-
Trypanosoma cruzi	Q27793	-	-

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+	-	Trypanosoma cruzi	5,6,7,8-tetrahydrofolate + NADP+	-	?

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.0000094	-	4-((5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl)ethynyl)benzoic acid	pH 7.0	Trypanosoma cruzi
0.0000122	-	7-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]hept-6-ynoic acid	pH 7.0	Trypanosoma cruzi

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.0000225	-	pH 7.0	Trypanosoma cruzi	4-((5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl)ethynyl)benzoic acid
0.0000256	-	pH 7.0	Trypanosoma cruzi	7-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]hept-6-ynoic acid
0.0000515	-	pH 7.0	Trypanosoma cruzi	6-[[(2,5-diethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
0.000131	-	pH 7.0	Trypanosoma cruzi	2-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid
0.000183	-	pH 7.0	Trypanosoma cruzi	3-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid
0.000222	-	pH 7.0	Trypanosoma cruzi	3-((3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenoxy)methyl)benzoic acid
0.001255	-	pH 7.0	Homo sapiens	7-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]hept-6-ynoic acid
0.0021	-	pH 7.0	Trypanosoma cruzi	trimetrexate
0.0023	-	pH 7.0	Homo sapiens	6-[[(2,5-diethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
0.002898	-	pH 7.0	Homo sapiens	4-((5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl)ethynyl)benzoic acid
0.0062	-	pH 7.0	Homo sapiens	2-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid
0.014	-	pH 7.0	Homo sapiens	3-[(3-(3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl)prop-2-yn-1-yl)oxy]benzoic acid
0.019	-	pH 7.0	Homo sapiens	3-((3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenoxy)methyl)benzoic acid
0.248	-	pH 7.0	Homo sapiens	trimetrexate