Background: There are over 44 million persons who suffer with Alzheimer’s disease (AD)
worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study
is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking
studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy.
Among all AChEIs donepezil possesses lowest adverse effects, it can treat mild-moderate-severe AD
and only once-daily dosing is required. Therefore donepezil is recognized as a significant prototype for design
and development of new drug molecule.
Methods: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme
has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic
evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined.
Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme
and analyzed compounds.
Results: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all
the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six
compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by in-silico
study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, -
8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity
of - 6.32 kcal/mol.
Conclusion: Computer aided drug design approach has been playing an important role in the design and
development of novel anti- AD drugs. With the help of structure based drug design some novel analogues
of donepezil have been designed and the molecular docking studies with structure based ADME properties
prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed
compounds with target protein i. e. AChE has been evaluated and the resulting data from docking studies
explains that all of the newly designed analogues had significantly high affinity towards target protein
compared to donepezil as a reference ligand.