PMID- 23272099
OWN - NLM
STAT- MEDLINE
DCOM- 20130626
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 12
DP  - 2012
TI  - Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 
      interaction.
PG  - e51329
LID - 10.1371/journal.pone.0051329 [doi]
LID - e51329
AB  - BACKGROUND: Nucleotide excision repair (NER) removes many types of DNA lesions 
      including those induced by UV radiation and platinum-based therapy. Resistance to 
      platinum-based therapy correlates with high expression of ERCC1, a major element 
      of the NER machinery. The interaction between ERCC1 and XPA is essential for a 
      successful NER function. Therefore, one way to regulate NER is by inhibiting the 
      activity of ERCC1 and XPA. METHODOLOGY/PRINCIPAL FINDINGS: Here we continued our 
      earlier efforts aimed at the identification and characterization of novel 
      inhibitors of the ERCC1-XPA interaction. We used a refined virtual screening 
      approach combined with a biochemical and biological evaluation of the compounds 
      for their ability to interact with ERCC1 and to sensitize cells to UV radiation. 
      Our findings reveal a new validated ERCC1-XPA inhibitor that significantly 
      sensitized colon cancer cells to UV radiation indicating a strong inhibition of 
      the ERCC1-XPA interaction. CONCLUSIONS: NER is a major factor in acquiring 
      resistance to platinum-based therapy. Regulating the NER pathway has the 
      potential of improving the efficacy of platinum treatments. One approach that we 
      followed is to inhibit the essential interaction between the two NER elements, 
      ERCC1 and XPA. Here, we performed virtual screening against the ERCC1-XPA 
      interaction and identified novel inhibitors that block the XPA-ERCC1 binding. The 
      identified inhibitors significantly sensitized colon cancer cells to UV radiation 
      indicating a strong inhibition of the ERCC1-XPA interaction.
FAU - Barakat, Khaled H
AU  - Barakat KH
AD  - Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
FAU - Jordheim, Lars P
AU  - Jordheim LP
FAU - Perez-Pineiro, Rolando
AU  - Perez-Pineiro R
FAU - Wishart, David
AU  - Wishart D
FAU - Dumontet, Charles
AU  - Dumontet C
FAU - Tuszynski, Jack A
AU  - Tuszynski JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121214
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Culture Media)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Ligands)
RN  - 0 (XPA protein, human)
RN  - 0 (Xeroderma Pigmentosum Group A Protein)
RN  - 9007-49-2 (DNA)
RN  - EC 3.1.- (ERCC1 protein, human)
RN  - EC 3.1.- (Endonucleases)
SB  - IM
MH  - Cell Line, Tumor
MH  - Culture Media
MH  - DNA/metabolism
MH  - *DNA Repair
MH  - DNA-Binding Proteins/*antagonists & inhibitors
MH  - Endonucleases/*antagonists & inhibitors
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Kinetics
MH  - Ligands
MH  - Models, Chemical
MH  - Models, Molecular
MH  - Models, Statistical
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Conformation
MH  - Solubility
MH  - Static Electricity
MH  - Ultraviolet Rays
MH  - Xeroderma Pigmentosum Group A Protein/*antagonists & inhibitors
PMC - PMC3522735
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/12/29 06:00
MHDA- 2013/06/28 06:00
PMCR- 2012/12/14
CRDT- 2012/12/29 06:00
PHST- 2012/03/25 00:00 [received]
PHST- 2012/10/10 00:00 [accepted]
PHST- 2012/12/29 06:00 [entrez]
PHST- 2012/12/29 06:00 [pubmed]
PHST- 2013/06/28 06:00 [medline]
PHST- 2012/12/14 00:00 [pmc-release]
AID - PONE-D-12-08640 [pii]
AID - 10.1371/journal.pone.0051329 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(12):e51329. doi: 10.1371/journal.pone.0051329. Epub 2012 Dec 14.