Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening
文献类型：期刊论文
| 作者 | Chen, Shijie1; Wang, Yulan1; Zhou, Wen; Li, Shanshan2; Peng, Jianlong1; Shi, Zhe3; Hu, Junchi1; Liu, Yu-Chih3; Ding, Hong1 ; Lin, Yijyun3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2014-11-13 |
| 卷号 | 57期号:21页码:9028-9041 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm501134e |
| 文献子类 | Article |
| 英文摘要 | The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors. |
| WOS关键词 | TUMOR-SUPPRESSOR GENES ; SMALL-MOLECULE INHIBITORS ; CANCER-CELL LINES ; METHYLATION INHIBITORS ; EPIGENETIC THERAPY ; PROTEIN ; INSIGHTS ; COMPLEX ; REACTIVATION ; HYDRALAZINE |
| 资助项目 | Hi-Tech Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81202398] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[91229204] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002-005-012] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000344977400025 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276839]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Liu, Bo |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.China Pharmaceut Univ, Sch Sci, Lab Mol Design & Drug Discovery, Nanjing 210009, Peoples R China; 3.Shanghai ChemPartner Co Ltd, Shanghai 201203, Peoples R China; 4.Guangzhou Univ Chinese Med, Affiliated Hosp 2, Guangdong Prov Acad Chinese Med Sci, Guangzhou 510006, Guangdong, Peoples R China; 5.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Shijie,Wang, Yulan,Zhou, Wen,et al. Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening[J]. JOURNAL OF MEDICINAL CHEMISTRY,2014,57(21):9028-9041. |
| APA | Chen, Shijie.,Wang, Yulan.,Zhou, Wen.,Li, Shanshan.,Peng, Jianlong.,...&Luo, Cheng.(2014).Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening.JOURNAL OF MEDICINAL CHEMISTRY,57(21),9028-9041. |
| MLA | Chen, Shijie,et al."Identifying Novel Selective Non-Nucleoside DNA Methyltransferase 1 Inhibitors through Docking-Based Virtual Screening".JOURNAL OF MEDICINAL CHEMISTRY 57.21(2014):9028-9041. |
入库方式： OAI收割
来源：上海药物研究所
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