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Title

Screening and analysis of acetyl-cholinesterase (AChE) inhibitors in the context of Alzheimer’s disease

 

Authors

Mohd. Babu Khan1, Bhagath Kumar Palaka1, Tuleshwori Devi Sapam1, Dr. Naidu Subbarao2, Dr. Dinakara Rao Ampasala1*

 

Affiliation

1Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry-605014;

2School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India;

 

E-mail

ampasaladr@gmail.com, ampasaladr@bicpu.edu.in

 

Article Type

Hypothesis

 

Date

Received August 3, 2018; Revised August 19, 2018; Accepted August 19, 2018; Published August 31, 2018

 

Abstract

Acetyl-cholinesterase enzyme (AChE) is a known target for identifying potential inhibitors against Alzheimer diseases (AD). Therefore, it is of interest to screen AChE with the CNS-BBB database. An AChE enzyme is a member of hydrolase family is activated by acetylcholine (ACh), so, targeting the AChE enzyme with the potential inhibitor may block the binding of the ACh. In this study we carried out virtual screening of drug-like molecules from Chemical Diversity Database particularly CNS-BBB compounds, to identify potential inhibitors using Glide docking program. Top ranking ten compounds, which have lower Glide Score when compared to known drugs (Tacrine and Galantamine) for AChE. For top three molecules MD simulation was carried out and calculated binding free energy. We report the best binding compounds with AChE compared to known drugs (Taine and Galantamine) for AD. We further document the salient features of their molecular interaction with the known target. Three molecules (1-benzyl-3-(2-hydroxyethyl)-N-[2-(3-pyridyl)ethyl]-3-pyrrolidinecarboxamide, N-{3[benzyl(methyl)amino]propyl}-1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide, and 6-chloro-N-[2-(diethylamino)-2-phenylethyl]-4-oxo-4H-chromene-2-carboxamide) have -196.36, -204.27, -214.40 kJ/mol, binding free energy values respectively which are much lower than values calculated for the reference ligands Tacrine and Galantamine having -119.65 and -142.18 kJ/mol respectively. Thus these molecules can be very novel potential inhibitors against AChE involved in Alzheimer’s disease.

 

Keywords:

AChE, CNS-BBB database, Virtual Screening, MD simulations, Binding free energy, and FEL analysis.

 

Citation

Khan et al. Bioinformation 14(8): 414-429 (2018)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.