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

<h4>Background</h4>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 b...

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Autores principales:	Khaled H Barakat, Lars P Jordheim, Rolando Perez-Pineiro, David Wishart, Charles Dumontet, Jack A Tuszynski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/20ece2b4d4f641e686586a44680936bf
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spelling	oai:doaj.org-article:20ece2b4d4f641e686586a44680936bf2021-11-18T08:04:57ZVirtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.1932-620310.1371/journal.pone.0051329https://doaj.org/article/20ece2b4d4f641e686586a44680936bf2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23272099/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.Khaled H BarakatLars P JordheimRolando Perez-PineiroDavid WishartCharles DumontetJack A TuszynskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e51329 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Khaled H Barakat Lars P Jordheim Rolando Perez-Pineiro David Wishart Charles Dumontet Jack A Tuszynski Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.
format	article
author	Khaled H Barakat Lars P Jordheim Rolando Perez-Pineiro David Wishart Charles Dumontet Jack A Tuszynski
author_facet	Khaled H Barakat Lars P Jordheim Rolando Perez-Pineiro David Wishart Charles Dumontet Jack A Tuszynski
author_sort	Khaled H Barakat
title	Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
title_short	Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
title_full	Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
title_fullStr	Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
title_full_unstemmed	Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.
title_sort	virtual screening and biological evaluation of inhibitors targeting the xpa-ercc1 interaction.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/20ece2b4d4f641e686586a44680936bf
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Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.

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