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Computer aidded design of new inhibitors of acetylcholinesterase.
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1  Laboratório de Modelagem Computacional –LaModel, Instituto de Ciências Exatas –ICEx, Universidade Federal de Alfenas – UNIFAL-MG. Brasil


It is well known that the cholinergic deficiency contributes to the cognitive deterioration of Alzheimer’s Disease (AD) patients and that its pathways in the cerebral cortex are also compromised. In this work we use computational tools to design new and more powerful inhibitors of acetylcholinesterase (AChe). We made use of the de novo design and fragment-based drug design (FBDD). In the former approach, we started from reference drugs used in the AD treatment. These drugs were break into small pieces (fragments). These fragment were used as seed to grown new molecules or to be linked with other new fragments. In the latter approach, a library of fragments is docked in the active site of the enzyme. The interaction of each fragment is measured and they are organized by their affinity. The best ranked fragment are them linked between them to form new molecules with high degree of interaction with the active site of the enzyme. Using this strategy, we were able to produce a library of 2M new molecules. This library was filtered using as criterion the adsorption, distribution, metabolism and excretion (ADME) properties. The resulting library with around 6k molecules is filtered again using the Tanimoto similarity coefficient (structures with values greater than 0.85 were eliminated). The final library with 1.5k compound was submitted to docking studies. Finally, 10 compounds with better interaction energies than the reference compounds were obtained.

Keywords: Alzheimer’s Disease, acetylcholinesterase, de novo design, fragment docking
Comments on this paper
Giovanni Marzaro
Number of AChe structures used
Dear Authors,

a very interesting work on a very hot topic in medchem.

I have a question about the AChE structure used: why did you select only one protein structure? Did you consider the possibility to use more PDB structures to take into account the protein flexibility?

Many thanks
Ihosvany Camps
Many thanks for your comment Giovanni.

The last step in the modeling study was an Induced Fit Docking. This step is a protocol were different substeps are taken. Among this substeps, one is the consideration of the flexibility of the protein. So, there is no need to use different structures.

Details of Induced Fit Docking can be seen here:



Juan Castillo-Garit
complementary approach...
Dear Authors
Have you consider use other complementary studies? let say for example cheminformatics models to predict the activity/inactivity of the designed molecules. You can make this knid of work as a complementary approach to Docking studies. It is another way to see the problem and could give you useful information.

best regards
Ihosvany Camps
Thank for your comments Juan Alberto Castillo-Garit,

We only did Molecular Dynamics and re-score the best 10 molecules using X-Score.

But it could be a good idea to run that kind of complementary studies.