Identification of novel small molecule inhibitors of the XPA protein using in silico based screening

Tracy M. Neher, Sarah C. Shuck, Jing Yuan Liu, Jian-Ting Zhang, John Turchi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The nucleotide excision repair pathway catalyzes the removal of bulky adduct damage from DNA and requires the activity of more than 30 individual proteins and complexes. A diverse array of damage can be recognized and removed by the NER pathway including UV-induced adducts and intrastrand adducts induced by the chemotherapeutic compound cisplatin. The recognition of DNA damage is complex and involves a series of proteins including the xeroderma pigmentosum group A and C proteins and the UV-damage DNA binding protein. The xeroderma pigmentosum group A protein is unique in the sense that it is required for both transcription coupled and global genomic nucleotide excision repair. In addition, xeroderma pigmentosum group A protein is required for the removal of all types of DNA lesions repaired by nucleotide excision repair. Considering its importance in the damage recognition process, the minimal information available on the mechanism of DNA binding, and the potential that inhibition of xeroderma pigmentosum group A protein could enhance the therapeutic efficacy of platinum based anticancer drugs, we sought to identify and characterize small molecule inhibitors of the DNA binding activity of the xeroderma pigmentosum group A protein. In silico screening of a virtual small molecule library resulted in the identification of a class of molecules confirmed to inhibit the xeroderma pigmentosum group A protein-DNA interaction. Biochemical analysis of inhibition with varying DNA substrates revealed a common mechanism of xeroderma pigmentosum group A protein DNA binding to single-stranded DNA and cisplatin-damaged DNA.

Original languageEnglish
Pages (from-to)953-965
Number of pages13
JournalACS Chemical Biology
Volume5
Issue number10
DOIs
StatePublished - Oct 15 2010

Fingerprint

Xeroderma Pigmentosum Group A Protein
Computer Simulation
Screening
Molecules
DNA
DNA Repair
Proteins
Repair
Cisplatin
DNA Damage
Nucleotides
Small Molecule Libraries
DNA Adducts
Single-Stranded DNA
DNA-Binding Proteins
Platinum
Protein Binding
Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Identification of novel small molecule inhibitors of the XPA protein using in silico based screening. / Neher, Tracy M.; Shuck, Sarah C.; Liu, Jing Yuan; Zhang, Jian-Ting; Turchi, John.

In: ACS Chemical Biology, Vol. 5, No. 10, 15.10.2010, p. 953-965.

Research output: Contribution to journalArticle

Neher, Tracy M. ; Shuck, Sarah C. ; Liu, Jing Yuan ; Zhang, Jian-Ting ; Turchi, John. / Identification of novel small molecule inhibitors of the XPA protein using in silico based screening. In: ACS Chemical Biology. 2010 ; Vol. 5, No. 10. pp. 953-965.
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