中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
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
DOI10.1016/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

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