Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction

PLoS One. 2012;7(12):e51329. doi: 10.1371/journal.pone.0051329. Epub 2012 Dec 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Culture Media
  • DNA / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Endonucleases / antagonists & inhibitors*
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Ligands
  • Models, Chemical
  • Models, Molecular
  • Models, Statistical
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation
  • Solubility
  • Static Electricity
  • Ultraviolet Rays
  • Xeroderma Pigmentosum Group A Protein / antagonists & inhibitors*

Substances

  • Culture Media
  • DNA-Binding Proteins
  • Ligands
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • DNA
  • ERCC1 protein, human
  • Endonucleases

Grant support

The only source of funding for this project was the Allard Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.