Molecular modelling studies of acetylcholinesterase

The controversial role of electrostatic interactions in the process of steering of acetylcholine into the active site of acetylcholinesterases was investigated in this study. A novel methodology was implemented to simulate the process of recognition of acetylcholine by Torpedo Californica and both wild type and charge neutralized mutated Human AChE. The obtained results suggest the important role of coulombic interactions in the steering process. The steering process of selected irreversible AChE inhibitors was also simulated supporting the role of electrostatic interactions in the recognition process. A novel methodology was also employed to model the covalent adducts of Torpedo Californica and Human AChE\u27s with various organophosphate inhibitors and the interactions of the organophosphate moieties with the surrounding amino acid residues of the active sites of the modeled complexes were analyzed. Finally, an automated docking environment and methodology were designed and implemented in the prediction of the binding sites in Human AChE of three reversible acetyl cholinesterase inhibitors, clinically investigated for the treatment of Alzheimer\u27s type senile dementia. The results of the docking analysis reproduce the potency rank of the studied inhibitor molecules providing with a wealth of structural information consistent with similar studies on Torpedo Californica AChE. The developed tools and methodology can be directly applied in database screening for the discovery of new lead compounds