Cavalli_2004_J.Med.Chem_47_3991

Combined docking and molecular dynamics (MD) simulations were carried out in order to investigate the binding mode of propidium at the human acetylcholinesterase (HuAChE) peripheral site. Two different docking protocols followed by cluster analyses were performed, allowing the identification of five high-populated and low-energy configuration families. To dynamically explore the behavior of the ligand at the peripheral HuAChE binding site, six complexes (five low-energy and one high-energy) were submitted to 2.5 ns of MD simulations. The representative propidium/HuAChE binding modes were chosen on the basis of both the docking energy score and the dynamic stability of the complexes throughout the MD simulations. The most stable poses of propidium at HuAChE PAS were similar to those experimentally determined with the murine enzyme. We therefore suggest that the present modeling protocol might be used in the dynamic investigation of the interactions of a small-molecule inhibitor with a surface-like binding site of a protein. Finally, because of the biological relevance of the target studied here, the present results can be of interest for the rational design of molecules potentially useful in the treatment of the Alzheimer's disease.