Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors

doi:10.1016/j.bioorg.2018.10.057

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	Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors
	Cheng, Zhi-Qiang 4; Zhu, Kong-Kai 1,4; Zhang, Juan4 ; Song, Jia-Li 4; Muehlmann, Luis Alexandre 2,3; Jiang, Cheng-Shi 4; Liu, Chang-Liang 5,6; Zhang, Hua 4
刊名	Bioorganic chemistry
	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
内容类型	期刊论文
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.