[1]杨雪雨,赵腾腾,董珂珂,等.分子模拟研究多奈哌齐及其衍生物对AChE/BChE的抑制活性和选择性[J].南京师范大学学报(自然科学版),2017,40(03):123.[doi:10.3969/j.issn.1001-4616.2017.03.018]
 Yang Xueyu,Zhao Tengteng,Dong Keke,et al.Studies on the Bioactivity and Selectivity of Pyridonepezils to AChE/BChE by Molecular Modeling[J].Journal of Nanjing Normal University(Natural Science Edition),2017,40(03):123.[doi:10.3969/j.issn.1001-4616.2017.03.018]
点击复制

分子模拟研究多奈哌齐及其衍生物对AChE/BChE的抑制活性和选择性()
分享到:

《南京师范大学学报》(自然科学版)[ISSN:1001-4616/CN:32-1239/N]

卷:
第40卷
期数:
2017年03期
页码:
123
栏目:
·化学·
出版日期:
2017-09-30

文章信息/Info

Title:
Studies on the Bioactivity and Selectivity of Pyridonepezils to AChE/BChE by Molecular Modeling
文章编号:
1001-4616(2017)03-0123-05
作者:
杨雪雨赵腾腾董珂珂朱小蕾
南京工业大学化工学院,材料化学工程国家重点实验室,江苏 南京 210009
Author(s):
Yang XueyuZhao TengtengDong KekeZhu Xiaolei
State Key Laboratory of Materials-Oriented Chemical Engineering,College of Chemistry and Chemical Engineering,Nanjing University of Technology,Nanjing 210009,China
关键词:
胆碱酯酶多奈哌齐分子动力学模拟MM-PBSA方法选择性
Keywords:
cholinesterasedonepezilmolecular dynamics simulationMM-PBSA methodselectivity
分类号:
O643.1
DOI:
10.3969/j.issn.1001-4616.2017.03.018
文献标志码:
A
摘要:
乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)是具有高度同源的蛋白质,其在胆碱能神经系统中发挥着重要的作用. 在本文中,我们选取了已投入临床使用的药物多奈哌齐及其吡啶衍生物对AChE/BChE的抑制活性和选择性进行了研究. 我们采用MM-PBSA方法对两种抑制剂与AChE/BChE间的相互作用能进行了计算,结果表明范德华相互作用在总的结合能中贡献最大,且多奈哌齐的吡啶衍生物表现出比多奈哌齐更高的抑制活性以及选择性,所得计算结果与实验上抑制剂的抑制常数有较好的吻合.
Abstract:
Acetylcholinesterase(AChE)and butyrylcholinesterase(BChE)are highly homologous proteins and play important roles in the cholinergic nervous system. In current work,we investigate the bioactivity and selectivity of the pyridonepezils to AChE/BChE. The binding interactions between the two inhibitors and AChE/BChE are examined based on the MM-PBSA method. The results demonstrate that the van der Waals interactions have the largest contributions to the binding free energy,and the pyridonepezil exhibits higher bioactivity and selectivity to AChE/BChE compared to donepezil. The rank of calculated binding free energies is in good agreement with experimental inhibiting constants of the two inhibitors.

参考文献/References:

[1] FERRI C P,PRINCE M,BRAYNE C,et al. Global prevalence of dementia:a Delphi consensus study[J]. Lancet,2005,366(9 503):2 112-2 117.
[2]REITZ C,MAYEUX R. Alzheimer disease:epidemiology,diagnostic criteria,risk factors and biomarkers[J]. Biochem pharmacol,2014,88(4):640-651.
[3]MUSSELE S V,BASTARD N L,VERMEIREN Y,et al. Behavioral symptoms in mild cognitive impairment as compared with Alzheimer’s disease and healthy older adults[J]. Int J Geriatr Psych,2013,28(3):265-275.
[4]SPERLING R A,DICKERSON B C,PIHLAJAMAKI M,et al. Functional alterations in memory networks in early Alzheimer’s disease[J]. Neuromol Med,2010,12(1):27-43.
[5]LAZZARO V D,OLIVIERO A,PILATO F,et al. Neurophysiological predictors of long term response to AChE inhibitors in AD patients[J]. J Neurol Neurosur Psychiatry,2005,76(8):1 064-1 069.
[6]MOLINUEVO J L,BERTHIER M L,RAMI L. Donepezil provides greater benefits in mild compared to moderate Alzheimer’s disease:implications for early diagnosis and treatment[J]. Arch gerontol geriat,2011,52(1):18-22.
[7]TSUNO N. Donepezil in the treatment of patients with Alzheimer’s disease[J]. Expert Rev Neurother,2009,9(5):591-598.
[8]SAMADI A,ESTRADA M,PEREZ C,et al. Pyridonepezils,new dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease:synthesis,biological assessment,and molecular modeling[J]. Eur J Med Chem,2012,57:296-301.
[9]KRYGER G,SILMAN I,SUSSMAN J L. Structure of acetylcholinesterase complexed with E2020(Aricept):implications for the design of new anti-Alzheimer drugs[J]. Structure with folding and design,1999,7(3):297-307.
[10]NICOLET Y,LOCKRIDGE O,MASSON P,et al. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products[J]. J Biol Chem,2003,278(42):41 141-41 147.
[11]MORRIS G M,GOODSELL D S,HALLIDAY R S,et al. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function[J]. J Comput Chem,1998,19(14):1 639-1 662.
[12]CASE D A,CHEATHAM T A,SIMMERLING C L,et al. AMBER10[M]. San Francisco:University of California,2008.
[13]ANDERSEN H C. Molecular dynamics simulations at constant pressure and/or temperature[J]. J Chem Phys,1980,72(4):2 384-2 393.
[14]KOTHANDAN G,CHO S J. Prediction of binding free energy calculation using Molecular Mechanics/Poisson-Boltzmann Surface Area(MM-PBSA)method in drug discovery:a short review[J]. J Chosun Natural Sci,2012,5(4):216-219.
[15]SAIZ U L,CABRERA M A,FROEYEN M. Exploring the conformational changes of the ATP binding site of gyrase B from Escherichia coli complexed with different established inhibitors by using molecular dynamics simulation:protein-ligand interactions in the light of the alanine scanning and free energy decomposition methods[J]. J Mol Graph Model,2011,29(5):726-739.
[16]PAIS F S,RUY PDE C,OLIVEIRA G,et al. Assessing the efficiency of multiple sequence alignment programs[J]. Algorithm Mol Biol,2014,9(4):1-8.

相似文献/References:

[1]赵腾腾,杨雪雨,王亚莉,等.分子模拟研究1,3,4-噻二唑类衍生物 对AChE/BChE的生物活性和选择性机理[J].南京师范大学学报(自然科学版),2018,41(01):55.[doi:10.3969/j.issn.1001-4616.2018.01.011]
 Zhao Tengteng,Yang Xueyu,Wang Yali,et al.Studies on Mechanism of Bioactivity and Selectivity of 1,3,4-Thiadiazol Inhibitors to AChE/BChE by Molecular Dynamic[J].Journal of Nanjing Normal University(Natural Science Edition),2018,41(03):55.[doi:10.3969/j.issn.1001-4616.2018.01.011]

备注/Memo

备注/Memo:
收稿日期:2016-06-24.
基金项目:国家自然科学基金项目(20706029、 20876073、 91434109).
通讯联系人:朱小蕾,博士,教授,研究方向:分子模拟的研究工作. E-mail:xlzhu@njtech.edu.cn
更新日期/Last Update: 2017-09-30