Abstract
When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level. We searched for possible binding sites of Srx using a binding site prediction method and uncovered two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, we confirmed that J14 binds to the ATP binding site; therefore, J14 acts as a competitive inhibitor of ATP, settling the question of the two mechanisms. Based on the inhibition mechanism revealed at the atomic level, we designed several derivatives of J14, which led to LMT-328 (4-(((4-(4-(2-Chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid), which is possibly an even more potent inhibitor than J14.
| Original language | English |
|---|---|
| Pages (from-to) | 208-215 |
| Number of pages | 8 |
| Journal | Journal of Molecular Graphics and Modelling |
| Volume | 92 |
| DOIs | |
| Publication status | Published - 2019 Nov 1 |
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Keywords
- Chemical study
- Molecular dynamics simulation
- Molecular modeling
- Peroxiredoxin
- Sulfiredoxin
ASJC Scopus subject areas
- Spectroscopy
- Physical and Theoretical Chemistry
- Computer Graphics and Computer-Aided Design
- Materials Chemistry
Cite this
Elucidation of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors. / Kim, Minsup; Kwon, Jinsun; Goo, Ja il; Choi, Yongseok; Cho, Art E.
In: Journal of Molecular Graphics and Modelling, Vol. 92, 01.11.2019, p. 208-215.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Elucidation of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors
AU - Kim, Minsup
AU - Kwon, Jinsun
AU - Goo, Ja il
AU - Choi, Yongseok
AU - Cho, Art E.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level. We searched for possible binding sites of Srx using a binding site prediction method and uncovered two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, we confirmed that J14 binds to the ATP binding site; therefore, J14 acts as a competitive inhibitor of ATP, settling the question of the two mechanisms. Based on the inhibition mechanism revealed at the atomic level, we designed several derivatives of J14, which led to LMT-328 (4-(((4-(4-(2-Chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid), which is possibly an even more potent inhibitor than J14.
AB - When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level. We searched for possible binding sites of Srx using a binding site prediction method and uncovered two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, we confirmed that J14 binds to the ATP binding site; therefore, J14 acts as a competitive inhibitor of ATP, settling the question of the two mechanisms. Based on the inhibition mechanism revealed at the atomic level, we designed several derivatives of J14, which led to LMT-328 (4-(((4-(4-(2-Chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid), which is possibly an even more potent inhibitor than J14.
KW - Chemical study
KW - Molecular dynamics simulation
KW - Molecular modeling
KW - Peroxiredoxin
KW - Sulfiredoxin
UR - http://www.scopus.com/inward/record.url?scp=85070113721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070113721&partnerID=8YFLogxK
U2 - 10.1016/j.jmgm.2019.07.018
DO - 10.1016/j.jmgm.2019.07.018
M3 - Article
AN - SCOPUS:85070113721
VL - 92
SP - 208
EP - 215
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
SN - 1093-3263
ER -