Identification and Assessments of Novel and Potent Small-Molecule Inhibitors of EED-EZH2 Interaction of Polycomb Repressive Complex 2 by Computational Methods and Biological Evaluations
文献类型：期刊论文
| 作者 | Zhu, Kongkai2; Du, Daohai1; Yang, Rui2; Tao, Hongrui2; Zhang, Hua2 |
| 刊名 | CHEMICAL & PHARMACEUTICAL BULLETIN
 |
| 出版日期 | 2020 |
| 卷号 | 68期号:1页码:58-63 |
| 关键词 | polycomb repressive complex 2 EZH2-EED interaction inhibitor virtual screening molecular dynamics simulation |
| ISSN号 | 0009-2363 |
| 通讯作者 | Zhang, Hua(bio_zhangh@ujn.edu.cn) |
| 英文摘要 | Polycomb repressive complex 2 (PRC2) is an attractive drug target for anti-cancer treatment. Among the three core subunits (EZH2, EED and SUZ12) of PRC2, EZH2 is the catalytic subunit that methylates histone 113 lysine 27 (H3K27), while EED is the regulatory subunit. Besides the small-molecule inhibitors of EZH2, those targeting the protein-protein interaction (PPI) between EZH2 and EED have also been reported. Here, for the first time, we have identified the key residues that contributed most to the EED-EZH2 binding affinity by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations based on the 200 ns molecular dynamics simulation. Moreover, we report the identification of two novel and potent small-molecule inhibitors (35 and 49) of EZH2-EED interaction (bottom interaction surface) by virtual screening and biological evaluations. Binding modes of the two identified molecules with EED were probed by molecular docking. Additionally, 35 and 49 displayed cellular antiproliferative activity against diffuse large B-cell lymphoma (DLBCL) cancer cell line Toledo whose cell growth was driven by aberrant PRC2 activity. Our findings have provided structural insights for the design of novel EZH2-EED interaction inhibitors to regulate the activity of PRC2 complex. |
| WOS关键词 | METHYLTRANSFERASE ACTIVITY ; EZH2-EED INTERACTION ; SELECTIVE INHIBITOR ; ACCURATE DOCKING ; CANCER-CELLS ; METHYLATION ; DISCOVERY ; LYMPHOMA ; H3K27 ; GLIDE |
| 资助项目 | National Natural Science Foundation of China[81803438] ; Shandong provincial key research and development program[2019GSF108043] ; Shandong Provincial Natural Science Foundation[JQ201721] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000504947200004 |
| 出版者 | PHARMACEUTICAL SOC JAPAN |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/282239]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Hua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Kongkai,Du, Daohai,Yang, Rui,et al. Identification and Assessments of Novel and Potent Small-Molecule Inhibitors of EED-EZH2 Interaction of Polycomb Repressive Complex 2 by Computational Methods and Biological Evaluations[J]. CHEMICAL & PHARMACEUTICAL BULLETIN,2020,68(1):58-63. |
| APA | Zhu, Kongkai,Du, Daohai,Yang, Rui,Tao, Hongrui,&Zhang, Hua.(2020).Identification and Assessments of Novel and Potent Small-Molecule Inhibitors of EED-EZH2 Interaction of Polycomb Repressive Complex 2 by Computational Methods and Biological Evaluations.CHEMICAL & PHARMACEUTICAL BULLETIN,68(1),58-63. |
| MLA | Zhu, Kongkai,et al."Identification and Assessments of Novel and Potent Small-Molecule Inhibitors of EED-EZH2 Interaction of Polycomb Repressive Complex 2 by Computational Methods and Biological Evaluations".CHEMICAL & PHARMACEUTICAL BULLETIN 68.1(2020):58-63. |
入库方式： OAI收割
来源：上海药物研究所
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