|Table of Contents|

Studies on Mechanism of Bioactivity and Selectivity of 1,3,4-ThiadiazolInhibitors to AChE/BChE by Molecular Dynamic(PDF)

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

Issue:
2018年01期
Page:
55-
Research Field:
·化学·
Publishing date:

Info

Title:
Studies on Mechanism of Bioactivity and Selectivity of 1,3,4-ThiadiazolInhibitors to AChE/BChE by Molecular Dynamic
Author(s):
Zhao TengtengYang XueyuWang YaliZhu Xiaolei
State Key Laboratory of Materials-Oriented Chemical Engineering,College of Chemical Engineering,Nanjing Tech University,Nanjing 210009,China
Keywords:
cholinesterase134-thiadiazol inhibitorsmolecular dynamics simulationMM-PBSA methodselectivity
PACS:
O643.1
DOI:
10.3969/j.issn.1001-4616.2018.01.011
Abstract:
Acetylcholinesterase(AChE)and butyrylcholinesterase(BChE)both belonging to the family of cholinesterases(ChEs),which differ in their catalytic properties and inhibition patterns,are highly homologous proteins and play important roles in the cholinergic nervous system. Revealing selectivity mechanism of inhibitors to cholinesterases is an important issue to develop potential Alzheimer’s drugs. In current work,we investigate the bioactivity and selectivity of three 1,3,4-thiadiazol inhibitors to AChE/BChE. The binding interactions between the three inhibitors and AChE/BChE are examined based on the MM-PBSA method. The results demonstrate that three kinds of inhibitors show higher activity to AChE than BChE,and illustrate that the three inhibitors can inhibit AChE selectively. The rank of calculated binding free energies is in good agreement with experimental inhibiting constants of the three inhibitors.

References:

[1] CHEN Y,LIN H,YANG H,et al. Discovery of new acetylcholinesterase and butyrylcholinesterase inhibitors through structure-based virtual screening[J]. Rsc advances,2017,7:3 429-3 438.
[2]ZHANG C,DU Q Y,CHEN L D,et al. Design,synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease[J]. European journal of medicinal chemistry,2016,116:200-209.
[3]CHEN X,FANG L,LIU J J,et al. Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine[J]. Journal of physical chemistry B,2011,115:1 315-1 322.
[4]Di LAZZARO V,OLIVIERO A,PILATO F,et al. Neurophysiological predictors of long term response to AChE inhibitors in AD patients[J]. Journal of neurology,neurosurgery,and psychiatry,2005,76:1 064-1 069.
[5]CAMPS P,FORMOSA X,GALDEANO C,et al. Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates[J]. Chem Biol Interact,2010,187:411-415.
[6]SUGIMOTO H,YAMANISHI Y,IIMURA Y,et al. Donepezil hydrochloride(E2020)and other acetylcholinesterase inhibitors[J]. Current medicinal chemistry,2000,7:303-339.
[7]MARCO L,do CARMO C,GALANTHAMINE M. A natural product for the treatment of Alzheimer’s disease[J]. Recent patents on CNS drug discovery,2006(1):105-111.
[8]BONO G F,SIM?O S D P,BATISTELA M S,et al. Furtado-alle butyrylcholinesterase:K variant,plasma activity,molecular forms and rivastigmine treatment in Alzheimer’s disease in a Southern Brazilianpopulation[J]. Neurochemistry international,2015,81:57-62.
[9]SKRZYPEK A,MATYSIAK J,NIEWIADOMY A,et al. Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors[J]. European journal of medicinal chemistry,2013,62:311-319.
[10]KRYGER G S 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.
[11]NICOLET Y,LOCKRIDGE O,MASSON P,et al. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products[J]. The journal of biological chemistry,2003,278:41 141-41 147.
[12]GARRETT M M,DAVID S G,ROBERT S H,et al. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function[J]. Journal of computational chemistry,1998,19:1 639-1 662.
[13]CORNELL W D,CIEPLAK P,BAYLY C I,et al. A second generation force field for the simulation of proteins,nucleic acids,and organic molecules[J]. Journal of the American chemical society,1995,117:5 179-5 197.
[14]WANG JM,WOLF R M,CALDWELL J W,et al. Development and testing of a general amber force field[J]. Journal of computational chemistry,2004,25:1 157-1 174.
[15]JORGENSEN W L,CHANDRASEKHAR J,MADURA J D,et al. Comparison of simple potential functions for simulating liquid water[J]. The journal of chemical physics,1983,79:926-935.
[16]ANDERSEN H C. Molecular dynamics simulations at constant pressure and/or temperature[J]. The journal of chemical physics,1980,72:2 384-2 393.
[17]KUMARI R,KUMAR R,LYNN A. g_mmpbsa-a GROMACS tool for high-throughput MM-PBSA Calculations[J]. Journal of chemical information and modeling,2014,54:1 951-1 962.
[18]SAíZ 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[J]. J Mol Graph Model,2011,29:726-739.

Memo

Memo:
-
Last Update: 2018-03-31