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 | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Homo sapiens |
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 | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | Q9BYN0 | - |
- |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
carcinoma cell | - |
Homo sapiens | - |
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 | Comment | Organism |
---|---|---|
Srx | - |
Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
ATP | - |
Homo sapiens | |
thioredoxin | - |
Homo sapiens |
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 | 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 |