Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study
文献类型：期刊论文
| 作者 | Siu, Fung-Ming; Pommier, Yves |
| 刊名 | NUCLEIC ACIDS RESEARCH
 |
| 出版日期 | 2013 |
| 英文摘要 | Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. Thesequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and nucleotide at the +1 position of the cleavage site was the major (favorable) contributor to the total binding energy. Mechanistic insights gained by a potential of mean force analysis implicated that the drug dissociation step was associated with the sequence selectivity. Pharmaceutical insights gained by our molecular dynamics analyses explained why LMP-776, an indenoisoquinoline derivative under clinical development at the National Institutes of Health, displays different sequence selectivity when compared with camptothecin and its clinical derivatives. |
| 收录类别 | SCI |
| 原文出处 | http://nar.oxfordjournals.org/content/41/22/10010.short |
| 语种 | 英语 |
| 源URL | [http://ir.siat.ac.cn:8080/handle/172644/5040]  |
| 专题 | 深圳先进技术研究院_数字所 |
| 作者单位 | NUCLEIC ACIDS RESEARCH |
| 推荐引用方式 GB/T 7714 | Siu, Fung-Ming,Pommier, Yves. Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study[J]. NUCLEIC ACIDS RESEARCH,2013. |
| APA | Siu, Fung-Ming,&Pommier, Yves.(2013).Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.NUCLEIC ACIDS RESEARCH. |
| MLA | Siu, Fung-Ming,et al."Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study".NUCLEIC ACIDS RESEARCH (2013). |
入库方式： OAI收割
来源：深圳先进技术研究院
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