Int. J. Bioinformatics and Biological Sci.: v.2 n.1&2, p. 111-126. March and June 2014

fragment based de novo Design and aDmE/t analysis

of Dual Binding Site acetylcholinesterase Inhibitors for

alzheimer’s Disease

Shikhar gupta 1 and c gopi mohan 2*

1 Department of Pharmacoinformatics, National Institute of Pharmaceutical Education

and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, INDIA

Present address: 2 Amrita Centre for Nanosciences and Molecular Medicine, Amrita

Institute of Medical Sciences and Research Centre, Kochi- 682 041, Kerala State, INDIA

*Corresponding author: C Gopi Mohan, cgopimohan@yahoo.com

abstract

Fragment-based de novo design has been successfully carried out to identify

novel dual binding site acetylcholinesterase inhibitors. Dataset consists of 18

co-crystallized inhibitors of the acetylcholinesterase enzyme from protein data

bank. They were dissected into 31 chemically diverse and commercially available

fragments. The newly generated compounds have been filtered through detailed

ADMET analysis followed by molecular docking experiment. Finally, synthesis

accessibility of the new leads was predicted by SYLVIA software. We identified

15 potential leads from the present study. These virtual screened compounds are

expectedtobeimportantleadsforthesearchofdualbindingsiteacetylcholinesterase

inhibitors and may provide invaluable insights to further understand the structural

basis of catalysis and inhibition of acetylcholinesterase enzyme.

Keywords: Alzheimer’s disease; acetylcholinesterase; fragment-based; Docking

Alzheimer’s disease (AD), the most common form of dementia is an age-related

neurodegenerative disorder characterized by progressive memory loss and other

cognitive impairments (Goedert et al , 2006). Although the etiology of AD is

unknown, histopathological hallmarks such as β-amyloid (Aβ) deposits, tau (τ) -

protein aggregation, oxidative stress, and low levels of acetylcholine (ACh) seem

to play significant role (Querfurth et al , 2010). So far, the cholinergic hypothesis

is still the practical approach for treating AD. Cholinesterase inhibitors can reduce

AD symptoms by inhibiting acetylcholinesterase (AChE), the enzyme responsible

for the hydrolysis of ACh at the synaptic cleft (Racchi et al , 2004). Hence,

acetylcholinesterase inhibitors (AChEIs) are widely used to alleviate symptoms of

moderate AD patients (Barril et al , 2001). At present, several AChEIs, viz. tacrine,

rivastigmine, donepezil and galanthamine have been approved by FDA for the