In Silico Design of Inhibitors for beta-Secretase: Implications for Alzheimer’s Disease

Order of Publishing in Issue: 
10
Volume :7
Issue :1
January, 2013
Page No: 
558-566
Authors: 
S. Sai Madhukar [1], Anand Solomon [2], Viswanath Das [3], K. Anil Kumar [4] and S. Krupanidhi [6]*
Address: 
[1] Department of Health Informatics, Karolinska Institute of Medical Sciences, Stockholm, Sweden
Address: 
[2] Sankar Foundation Research Institute, Vishakapatnam 530047, India
Address: 
[3] School of Biological Sciences and Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
Address: 
[4] Tata Chemicals Ltd, Innovation Center, Pune 412108, India, 6 Department of Biotechnology, Vignan University, Vadlamudi 522213. India.

Abstract:  β-secretase is regarded as one of the best characterized targets for Alzheimer’s disease therapy. β-secretase 1 protease plays an important role in cleaving amyloid precursor protein and further the formation of pathogenic β-amyloid plaques in the brain, thereby causing Alzheimer’s disease. The present work reports the docking studies of a series of analogues based derivatives of phenyl-piperazine, cyclic urea, N-phenyl-1-arylamide and Nphenylbenzenesulfonamide. The structure of âsecretase 1 complexed with a ligand, 2-amino- 6-propylpyrimidin-4(3H)-one was retrieved from Protein Data Bank and used in the present study. All the derivatives and clinically used drugs for Alzheimer’s disease, such as, tacrine, razadyne, exelon and aricept were energy minimized and docked with the receptor. The docked positions of all derivatives were compared with tacrine as the standard drug. Four of the derivatives showed better docking score and identical hydrogen bonds with that of tacrine.

Keywords: 
β-secretase, amyloid precursor protein, β-amyloid plaques, phenyl-piperazine, cyclic urea, N-phenyl-1-arylamide, Nphenylbenzenesulfonamide.
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