Identification of Novel Small Molecule Inhibitors of the XPA Protein Using in Silico Based Screening
Identification of Novel Small Molecule Inhibitors of the XPA Protein Using in Silico Based Screening
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DOI：
10.1021/cb1000444
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Turchi, John J.
中科院分区：
文献类型：
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作者：
Neher, Tracy M.;Shuck, Sarah C.;Turchi, John J.
核苷酸切除修复途径催化去除 DNA 中的大量加合物损伤，需要 30 多种单独的蛋白质和复合物的活性。 NER 途径可以识别并消除多种损伤，包括紫外线诱导的加合物和化疗化合物顺铂诱导的链内加合物。 DNA 损伤的识别非常复杂，涉及一系列蛋白质，包括猪干皮病 A 组和 C 组蛋白以及紫外线损伤 DNA 结合蛋白。着色性干皮病 A 组蛋白是独特的，因为它是转录偶联和整体基因组核苷酸切除修复所必需的。此外，着色性干皮病A组蛋白是去除通过核苷酸切除修复修复的所有类型的DNA损伤所必需的。考虑到其在损伤识别过程中的重要性、有关 DNA 结合机制的可用信息极少，以及抑制着色性干皮病 A 组蛋白可以增强铂类抗癌药物治疗效果的潜力，我们试图鉴定和表征着色性干皮病 A 组蛋白 DNA 结合活性的小分子抑制剂。对虚拟小分子库进行计算机筛选，鉴定出一类被证实可抑制着色性干皮病 A 组蛋白-DNA 相互作用的分子。对不同 DNA 底物的抑制作用的生化分析揭示了着色性干皮病 A 组蛋白 DNA 与单链 DNA 和顺铂损伤的 DNA 结合的共同机制。
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 pignnentosum 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.