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Literature summary extracted from

  • Srinivasan, B.; Skolnick, J.
    Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors (2015), FEBS J., 282, 1922-1938 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
1.5.1.3 drug development the enzyme represents an attractive target for inhibitor design to disrupt systems that require rapid DNA turnover, e.g. proliferating cancer cells and pathogenic microbes Escherichia coli

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.3 1-(4-nitrophenyl)-3-[4-[4-[(4-nitrophenyl)carbamoylamino]phenoxy]phenyl]urea NSC80735, complete inhibition at 1 mM Escherichia coli
1.5.1.3 1-N,4-N-bis(4-aminophenyl)benzene-1,4-dicarboxamide NSC55152, complete inhibition at 1 mM Escherichia coli
1.5.1.3 11H-benzo[b][1]benzazepine NSC123458, 87% inhibition at 1 mM Escherichia coli
1.5.1.3 6,7-bis(4-aminophenyl)pteridine-2,4-diamine NSC61642 Escherichia coli
1.5.1.3 7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine NSC309401, AMPQD, a substrate analogue with the quinazoline-1, 3-diamine group, tight-binding inhibitor, complete inhibition at 1 mM, competitive inhibition of dihydrofolate binding. Potently inhibits the enzyme by competitive displacement of the substrate dihydrofolic acid, uncompetitive inhibition versus NADPH, the inhibitor has a markedly increased affinity for the NADPH-bound form of the enzyme. The mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model Escherichia coli
1.5.1.3 7H-pyrrolo(3,2-f)quinazoline-1,3-diamine NSC339578 Escherichia coli
1.5.1.3 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine PQD, the lack of (4-aminophenyl)-methyl group at position 7 abolishes the slow-onset of inhibition Escherichia coli
1.5.1.3 methotrexate NSC740 Escherichia coli
1.5.1.3 methylbenzoprim NSC382035 Escherichia coli
1.5.1.3 additional information 7H-pyrrolo(3,2-f) quinazoline-1, 3-diamine (PQD) inhibition kinetics, overview Escherichia coli
1.5.1.3 pemetrexed NSC698037 Escherichia coli
1.5.1.3 pralatrexate NSC754230 Escherichia coli

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.5.1.3 additional information
-
 additional information Michaelis-Menten kinetics Escherichia coli

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+ Escherichia coli
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 r

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Escherichia coli P0ABQ4
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+
-
 Escherichia coli 5,6,7,8-tetrahydrofolate + NADP+
-
 r

Synonyms

EC Number Synonyms Comment Organism
1.5.1.3 DHFR
-
 Escherichia coli

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.3 NADP+
-
 Escherichia coli
1.5.1.3 NADPH
-
 Escherichia coli

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.5.1.3 additional information
-
 additional information inhibition kinetics, overview Escherichia coli
1.5.1.3 0.00000742
-
 7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine pH 7.3, 22°C Escherichia coli