Gupta and Mohan

selecting the compounds for further studies (Alavijeh et al , 2005). The physico-

chemical properties linked with compounds that have good blood-brain barrier

(BBB) penetration, optimum oral bioavailability, less or no toxicity and also

optimum solubility are the significant filters for selecting CNS active compounds

and there is a need for compounds with good pharmacokinetic properties (Klebe

et al , 2006). After carefully analyzing the ADMET properties of 3097 compounds

obtained from the FBDD strategy by LigBuilder, we finally selected 245 hits,

which were not showing any toxicity or less toxicity predicted by the DEREK

software (DEREK 10.0, U.K., 2010). Finally, hits having good pharmacokinetic

parameters and CNS activity were carried forward for structure-based evaluation

by molecular docking analysis at the dual binding site of the AChE enzyme.

molecular Docking and Synthesis accessibility prediction

Molecular docking is a computationally intensive structure-based technique

that generates and scores putative protein–ligand complexes according to their

calculated binding affinities (Mizutani et al , 2004). It has been successfully used

for identifying active compounds by filtering out those that do not fit into the

binding sites.Among the available crystal structures of theAChE enzyme, docking

studies were performed on the Torpedo californica AChE ( Tc AChE) structure

(PDB ID: 1EVE), considering that size and shape complementarity as well as the

dual binding site nature of the donepezil was similar to xanthostigmine. Tc AChE

has almost identical amino acid residues with the human AChE ( h AChE) (PDB

ID: 1B41) (Kryger et al , 2000) at both the CS and PAS, apart from the substitution

of F330 ( Tc ) with Y337 (human).

In order to further priorities the retrieve 245 hits from ADMET analysis and

subsequentlytoidentifythetrue/(orfalse)positivesdockingstudieswereperformed

at the dual binding site of AChE enzyme using GOLD program. Docking results

were reported as the highest scoring pose for each compound, and also on the

basis of their ability to form favorable interactions within the active site of AChE

enzyme. Based on the GOLD fitness scoring (GFS) function finally 15 compounds

were filtered as potential leads. These leads were further filtered using synthesis

accessibility studies. All the hit compounds possessed the GFS higher or equal to

52 kJ/mol (GFS ≥ 52 kJ/mol). The hit compounds showed excellent interactions

with the critical residues of PAS and CS of AChE. Different ADMET parameters

of these 15 compounds and their corresponding GFS values are given in Table 1.

The structures of these 15 lead compounds are presented in Figure 4.

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