University of Khartoum

Discovery of New Xanthones as Acetylcholine Esterase Inhibitors for Alzheimer’s Disease: In silico and In vitro Approach

Discovery of New Xanthones as Acetylcholine Esterase Inhibitors for Alzheimer’s Disease: In silico and In vitro Approach

Show full item record

Title: Discovery of New Xanthones as Acetylcholine Esterase Inhibitors for Alzheimer’s Disease: In silico and In vitro Approach
Author: Alawi, Mohammed Saeed Hamid
Abstract: Background: The emergence of peripheral side effects of currently available Acetylcholine Esterase Inhibitors (AChEIs) has called for the discovery of new leads targeting Alzheimer’s disease (AD). Nowadays, in silico methods have been widely accepted as fast tools for lead discovery. The aim of the study is to discover new AChEI lead for AD using In silico and in vitro methods. Methodology: For the first time, more than 8000 compounds, belonging to seven different chemical classes, were virtually screened, using SYBYL package, for their affinities towards AChE. Accessible molecules that showed higher affinities, judged by binding energies, were promoted to the next step. Eight xanthones were docked against 3D structure of AChE using Auto-Dock tools. The in silico revealed enzyme inhibition was further confirmed through in vitro assay following Ellman’s method. The potential enzyme inhibition was assessed using 0.05 M methanolic solution of tested xanthones. Finally, IC50 values were determined using EZ-fit software, statistically analyzed and discussed. Results: All tested xanthones exhibited promising binding energies (− 12.32 to – 8.00 Kcal/mol) with xanthone 7 being the best. The very low binding energy of xanthone 7 was attributed to its higher affinity to AChE. Xanthone 7 binds most of the key residues in esteratic, peripheral anionic, and catalytic anionic sub-sites. The protonated tertiary nitrogen exhibited binding, via pi-cation interactions, with histidine 440 in the esteratic sub-site and phenylalanine 330 and tryptophan 84 in the catalytic anionic sub-site. Furthermore, the peripheral anionic key residues tryptophan 279, tyrosine 70 and tyrosine 334 showed potential interaction with phenyl C−H of 7 via hydrophobic contact. These in silico findings agreed with the in vitro study where xanthone 7 showed the highest AChE inhibitory activity with IC50 = 0.2 µM. Furthermore, the calculated Log P of xanthone 7 was found to be 6.56 revealing its potential CNS penetrability. Conclusion: In silico and in vitro-guided study has resulted in discovery of xanthone 7 which is a new AChEI lead that is herein proposed to enter the development stage of AD new management.
Description: 63 Pages
URI: http://khartoumspace.uofk.edu/123456789/16982
Date: 2015-11-11


Files in this item

Files Size Format View

This item appears in the following Collection(s)

Show full item record

Share

Search DSpace


Browse

My Account