Gupta and Mohan

treatment of mild to moderate AD. On the other hand, memantine, an N -methyl

D -aspartate receptor blocker was approved for the management of moderate-to-

severe AD (Ibach et al , 2004). However, the clinical use of the AChEIs is limited

primarily due to their adverse effects and modest benefits towards AD patients.

Thus, novel and more effective treatment, includingAChEIs, needs to be developed

(Robichaud et al , 2006).

Recently, it has been reported thatAChE acceleratesAβ aggregation which initiated

a great interest towards the design and development of dual binding site inhibitors

of both CS consisting of the catalytic triad (S200, H440 and E327) together with

W84 and F330 and PAS including Y70, Y121 and W279 of AChE enzyme (i.e. a

dual binding site inhibitor) respectively. Moreover, it has been observed that dual

binding siteAChEIs are promising disease modifyingAD drug candidates because

they can simultaneously improve cognition and slows the Aβ aggregating activity

of AChE (Reyes et al , 2004).

Small-molecule drug discovery has always been a struggle of attrition, but in the

past few years pressure has mounted to increase efficiency at all stages of the

process. A potential solution for lead identification and optimization, fragment-

based drug discovery (FBDD), is becoming increasingly popular and emerged

as an important methodology for the generation of high quality leads (Rees et al ,

2004, Schulz et al , 2009, Zartler et al , 2005, Carr et al , 2005). In recent years,

fragment based compounds have already yielded very promising results in Phase

I clinical trials, including a Bcl-xL inhibitor from Abbott (ABT263) (Nienaber

et al , 2000), a kinase inhibitor from Astex (AT9283) (Gill et al , 2004), a PPAR

agonist from Plexxikon (PLX-204) (Card et al , 2005), and an HSP90 inhibitor

from a collaborative efforts of Novartis and Vernalis (NVP-AUY- 922) (Jensen et

al , 2008) respectively.

There are number of reported dual binding site AChEIs including bis(7)-tacrine

the heptylene- linked tacrine dimer, which possessed both optimal AChE

inhibitory potency and AChE/BuChE selectivity than tacrine (Pang et al , 1996),

bis-huperzine B (Feng et al , 2005), bis-5-amino-5,6,7,8-tetrahydroquinolinone

(Yu et al , 2008), and bis (-) nor-meptazinol (Xie et al , 2008) derivatives. The

bis-galanthamine linked by alkylene was more potent than galanthamine in the

AChE inhibition (Guillou et al , 2000). Also, hybrid of tacrine and huperzine A

shows higher activity and selectivity for AChE enzyme compared to tacrine and

huperzine A (Camps et al , 2000). The geometry of the active-site gorge of AChE,

with CS and PAS separated by 14 Å and located at its two extremities, makes it

a particularly suitable target for applying FBDD based approach (Sussman et al ,

1991).

The main objective of the present work was to develop a novel approach of FBDD

of dual binding site AChEIs that tries to fill the gap from fragment to ligand by

112

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