Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors
文献类型：期刊论文
| 作者 | Cheng, Zhi-Qiang4; Zhu, Kong-Kai1,4; Zhang, Juan4 ; Song, Jia-Li4; Muehlmann, Luis Alexandre2,3; Jiang, Cheng-Shi4; Liu, Chang-Liang5,6; Zhang, Hua4
|
| 刊名 | Bioorganic chemistry
 |
| 出版日期 | 2018-10-29 |
| 卷号 | 83页码:277-288 |
| ISSN号 | 1090-2120 |
| DOI | 10.1016/j.bioorg.2018.10.057 |
| 文献子类 | Article |
| 英文摘要 | A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/266827]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Jiang, Cheng-Shi; Liu, Chang-Liang; Zhang, Hua |
| 作者单位 | 1.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2.Institute of Biological Sciences, University of Brasília, Brasilia 70910900, Brazil; 3.Faculty of Ceilandia, University of Brasília, Brasilia 72220275, Brazil; 4.School of Biological Science and Technology, University of Jinan, Jinan 250022, China; 5.Cambrian Discovery Inc., Dover, MA 02115, USA; 6.Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA |
| 推荐引用方式 GB/T 7714 | Cheng, Zhi-Qiang,Zhu, Kong-Kai,Zhang, Juan,et al. Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors[J]. Bioorganic chemistry,2018,83:277-288. |
| APA | Cheng, Zhi-Qiang.,Zhu, Kong-Kai.,Zhang, Juan.,Song, Jia-Li.,Muehlmann, Luis Alexandre.,...&Zhang, Hua.(2018).Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors.Bioorganic chemistry,83,277-288. |
| MLA | Cheng, Zhi-Qiang,et al."Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors".Bioorganic chemistry 83(2018):277-288. |
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。