Designing dual binding site acetylcholinesterase inhibitors ……

the generated compounds to priorities the hits and to identify their dual binding

site nature.

molecular docking

GOLD (genetic optimization for ligand docking) program (Verdonk et al , 2003)

was used for docking study and the GOLD score option was selected as the

fitness function, denoted in short form as GOLD fitness score (GFS). The X-ray

coordinates of donepezil bound to the active site of the AChE enzyme were used

to define the active site region with an active site radius of 9.5 Å, by keeping

all the water molecules within the active site. The annealing parameters of van

der Waals and hydrogen-bonding interactions were considered within 4.0 Å and

2.5 Å, respectively, and other parameters were kept at the default setting. GOLD

has shown good reproducibility of experimentally observed binding conformation

of donepezil. In our study the superimposition of the docked donepezil onto the

crystallographic geometry yielded RMSD of 0.55 Å which satisfies our docking

protocol. Further, the best conformation of each selected compound comprises the

output on the basis of the GFS score and interactions formed between the ligands

and the active site. Finally promising leads were obtained by several methods

including ADMET analysis, molecular docking, and ranked compounds were

further evaluated for their synthesis accessibility by SYLVIA software (SYLVIA,

Molecular Networks GmbH).

Synthesis accessibility prediction

In order to evaluate the synthesis feasibility of our designed leads, SYLVIA

software was used (SYLVIA, Molecular Networks GmbH). SYLVIA scores

compounds from 1 (easy to synthesize) to 10 (difficult to synthesize) on the basis of

synthesis accessibility. Scoring function in SYLVIA includes- different structural

complexity measures, retro synthetic reaction fitness and different measures of

similarity to available starting material (Boda et al , 2007).

Results and Discussion

Fragment Generation

FBDD approach offers several advantages over conventional drug design methods

as fragment libraries are more diverse and synthetic resources are used more

efficiently(Congreve etal ,2008,Law etal ,2009).Eighteenrepresentativecomplex

structures were selected according to the structural diversity of the co-crystallized

ligands (Figure 1- Inhibitors 1 to 18 ). In the dissection process of inhibitors, the

fragments were chosen on the basis of their resemblance to the initial lead, and

their small size (<300 Da). Physicochemical analysis of the fragment seeds shows

that all fragments possessed properties consistent with the ‘‘Astex Rule of 3’’

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