Literature summary for 2.1.1.45 extracted from

Gangjee, A.; Qiu, Y.; Li, W.; Kisliuk, R.L.
Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates (2008), J. Med. Chem., 51, 5789-5797.

Application

Application	Comment	Organism
medicine	inhibition of TS and DHFR enzymes has found clinical utility as antitumor, antimicrobial and antiprotozoal agents	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
molecular modeling of complex with inhibitor N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid. The 6-methyl moiety of of the inhibitor makes important hydrophobic contacts with Trp109 and also serves to lock the 5-position side chain into favorable, low-energy conformations for thymidlyate synthase binding	Escherichia coli
molecular modeling of complex with inhibitor N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid. The 6-methyl moiety of of the inhibitor makes important hydrophobic contacts with Trp109 and also serves to lock the 5-position side chain into favorable, low-energy conformations for thymidlyate synthase binding	Toxoplasma gondii
molecular modeling of complex with inhibitor N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid. The 6-methyl moiety of of the inhibitor makes important hydrophobic contacts with Trp109 and also serves to lock the 5-position side chain into favorable, low-energy conformations for thymidlyate synthase binding	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
10-propargyl-5,8-dideazafolate	i.e. PDDF. Dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
10-propargyl-5,8-dideazafolate	i.e. PDDF. Dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
10-propargyl-5,8-dideazafolate	i.e. PDDF. Dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii
2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii
2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii
2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii
N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydrothieno(2,3-d)pyrimidin-5-yl)sulfanyl)benzoyl)-L-glutamic acid	-	Homo sapiens
N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid	-	Homo sapiens
N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii
pemetrexed	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme	Escherichia coli
pemetrexed	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme	Homo sapiens
pemetrexed	dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme	Toxoplasma gondii

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
5,10-methylenetetrahydrofolate + dUMP	Homo sapiens	inhibition of thymidylate synthase or of DHFR leads to thymineless death of eukaryotic organisms	7,8-dihydrofolate + dTMP	-	?

Organism

Organism	UniProt	Comment	Textmining
Escherichia coli	-	-	-
Homo sapiens	P04818	-	-
Toxoplasma gondii	-	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
5,10-methylenetetrahydrofolate + dUMP	-	Homo sapiens	7,8-dihydrofolate + dTMP	-	?
5,10-methylenetetrahydrofolate + dUMP	inhibition of thymidylate synthase or of DHFR leads to thymineless death of eukaryotic organisms	Homo sapiens	7,8-dihydrofolate + dTMP	-	?

Synonyms

Synonyms	Comment	Organism
TS-DHFR	-	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.000019	-	-	Escherichia coli	10-propargyl-5,8-dideazafolate
0.000036	-	-	Toxoplasma gondii	N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid
0.00004	-	-	Escherichia coli	N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid
0.00004	-	-	Homo sapiens	N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl]-L-glutamic acid
0.00004	-	potent inhibitor of human TS and of human DHFR, it is a novel dual TS-DHFR inhibitor, 330-fold more potent than pemetrexed	Homo sapiens	N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydrothieno(2,3-d)pyrimidin-5-yl)sulfanyl)benzoyl)-L-glutamic acid
0.000054	-	potent inhibitor of human TS and moderate inhibitor of human DHFR	Homo sapiens	N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
0.000085	-	-	Homo sapiens	10-propargyl-5,8-dideazafolate
0.00011	-	-	Homo sapiens	2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
0.00011	-	-	Homo sapiens	2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
0.00012	-	-	Homo sapiens	2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
0.00043	-	-	Toxoplasma gondii	10-propargyl-5,8-dideazafolate
0.0012	-	-	Toxoplasma gondii	2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
0.0012	-	-	Toxoplasma gondii	2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
0.0012	-	-	Escherichia coli	2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
0.0012	-	-	Toxoplasma gondii	2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
0.0023	-	-	Escherichia coli	2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
0.0024	-	-	Escherichia coli	2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
0.0028	-	-	Toxoplasma gondii	pemetrexed
0.0095	-	-	Homo sapiens	pemetrexed
0.076	-	-	Escherichia coli	pemetrexed