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Literature summary for 1.8.98.2 extracted from

  • Kim, M.; Kwon, J.; Goo, J.I.; Choi, Y.; Cho, A.E.
    Elucidation of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors (2019), J. Mol. Graph. Model., 92, 208-215 .
    View publication on PubMed

Inhibitors

Inhibitors Comment Organism Structure
4-(((4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid LMT-328, synthesis, a derivative of Jl4, more potent inhibitor than J14. The simulation, LMT-328 shows fast stabilization and tight binding with Srx. LMT-328 has a similar binding pose as the lead compound, J14, overview Homo sapiens
4-[[[4-[4-(2-chlorophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid J14, synthesis, interferes with the antioxidant activity of Srx at the molecular level. Identification of two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, it is confirmed that J14 binds to the ATP binding site, J14 acts as a competitive inhibitor of ATP. J14 can serve as a protein-protein interaction inhibitor that interferes with the binding between Prx and Srx Homo sapiens
additional information analysis of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors. Protein-ligand docking simulation of J14 and LMT-328, molecular dynamics simulation and binding free energy calculation, elucidation of the Srx inhibition mechanism, detailed overview Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin Homo sapiens
-
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9BYN0
-
-

Source Tissue

Source Tissue Comment Organism Textmining
carcinoma cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin
-
Homo sapiens peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
-
?

Synonyms

Synonyms Comment Organism
Srx
-
Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens
thioredoxin
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0067
-
against A549 cells, pH and temperature not specified in the publication Homo sapiens 4-(((4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid
0.0128
-
against A549 cells, pH and temperature not specified in the publication Homo sapiens 4-[[[4-[4-(2-chlorophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid

General Information

General Information Comment Organism
malfunction inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death Homo sapiens
physiological function Prxs, a type of the antioxidant peroxidases in cells, are including thioredoxin- and sulfiredoxin-dependent peroxidases, which play a crucial role in decreasing ROS levels in cells by taking part in the catalytic cycle. During the catalytic cycle for the reduction of Prx, a Cys active site residue (Cys-SH) of Prx is oxidized to a cysteine sulfenic acid (Cys-SOH) after forming a disulfide bond with the other cysteine of the adjacent Prx monomer. The oxidized Prx is reduced back to the initial form by thioredoxin (Trx). Moreover, the oxidized cysteine of Prx (Cys-SOH) can be oxidized again into sulfinic acid (Cys-SO2H). Srx exclusively reduces sulfinic acid to sulfenic acid by an ATP-dependent reaction catalyzed in presence of Mg2+. Antioxidant peroxidases, including Prx and Srx, are abundantly expressed in various cancers cells, and cancer cells are known to be more vulnerable to the toxicity of ROS under oxidative stress conditions than normal cells Homo sapiens