Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening
文献类型：期刊论文
| 作者 | Ma, Guang-Hui1,2,3; Ye, Yan2,4,5; Zhang, Dan1,6; Xu, Xin1; Si, Pei1,7; Peng, Jian-Long4; Xiao, Yong-Long1; Cao, Rui-Yuan8; Yin, Yu-Ling1; Chen, Jing1
|
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-11-29 |
| 卷号 | 124页码:981-991 |
| ISSN号 | 0223-5234 |
| 关键词 | HFMD EV71 3C(Pro) Non-peptidyl inhibitor Virtual screening |
| DOI | 10.1016/j.ejmech.2016.10.019 |
| 文献子类 | Article |
| 英文摘要 | Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications and even death. The pivotal role of EV71 3C(Pro) in the viral life cycle makes it an attractive target for drug discovery and development to treat HFMD. In this study, we identified novel EV71 3C(Pro) inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3C(Pro). The best inhibitor DC07090 exhibited the inhibition potency with an IC50 Value of 21.72 +/- 0.95 mu M without apparent toxicity (CC50 > 200 mu M). To explore structure-activity relationship of DC07090, 15 new derivatives were designed, synthesized and evaluated in vitro enzyme assay accordingly. Interestingly, four compounds showed inhibitory activities against EV71 3C(Pro) and only DC07090 inhibited EV71 replication with an EC50 value of 22.09 +/- 1.07 mu M. Enzyme inhibition kinetic experiments showed that the compound was a reversible and competitive inhibitor. The Ki value was determined to be 23.29 +/- 12.08 mu M. Further molecular docking, MD simulation and mutagenesis studies confirmed the binding mode of DC07090 and EV71 3C(Pro). Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC50 value of 27.76 +/- 0.88 mu M. Therefore, DC07090 represents a new non-peptidyl small molecule inhibitor for further development of antiviral therapy against EV71 or other picornaviruses. (C) 2016 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | MOUTH-DISEASE ; 3C-PROTEASE INHIBITORS ; ACCURATE DOCKING ; HAND ; FOOT ; DESIGN ; INFECTION ; CHILDREN ; CHINA ; RUPINTRIVIR |
| 资助项目 | National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[81573351] ; State Key Laboratory of Natural and Biomimetic Drugs[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000388544600076 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275793]  |
| 专题 | 药物化学研究室 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 药物发现与设计中心 生物技术药物研发中心（筹） 药理学第一研究室 |
| 通讯作者 | Zhou, Yu; Luo, Xiao-Min; Chen, Li-Li |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 5.Peking Univ, State Key Lab Nat & Biomimet Drugs, 38 Xueyuan Rd, Beijing 100191, Peoples R China; 6.Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drugs Design & Discovery, 103 Culture Rd, Shenyang 110016, Peoples R China; 7.Shanghai Normal Univ, Coll Life & Environm Sci, 100 Guilin Rd, Shanghai 200234, Peoples R China; 8.Beijing Inst Pharmacol & Toxicol, 27 Taiping Rd, Beijing 100850, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Guang-Hui,Ye, Yan,Zhang, Dan,et al. Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2016,124:981-991. |
| APA | Ma, Guang-Hui.,Ye, Yan.,Zhang, Dan.,Xu, Xin.,Si, Pei.,...&Shen, Xu.(2016).Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,124,981-991. |
| MLA | Ma, Guang-Hui,et al."Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 124(2016):981-991. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。