Study of Acetylcholinesterase and Butyrylcholinesterase (AChE/BuChE) Inhibition Using Molecular Modelling Methods

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that affects the majority of people worldwide. To date, there is no cure for the disease, so new therapeutic targets need to be identified and studied. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD treatment. In order to identify new inhibitors, a newly synthesized series containing thirty seven 2-hydroxy-N-phenylbenzamidederivatives were tested to study the inhibition of enzymes associated with this disease. Our work focuses on the use of molecular modeling methods based on molecular docking, QSAR and ADME property prediction. Our molecular docking results discussion is based on a number of parameters. Analysis of these obtained results showed that the ligands L18, L17 and L6 have a high inhibitory effect in the case of the enzyme AChE, while the ligands L6′, L30′ and L4′ have a high inhibitory effect in the case of the enzyme BuChE. In addition, the ADME-T properties calculation proved that these ligands respect the Lipinski, Veber and Egan rules, allowing us to select them as being probably the best inhibitors of Alzheimer’s disease (AD). Then, a QSAR model was developed to explain and predict the inhibitory activity of a series of compounds using different descriptors. This model has been validated by two methods: internal and external.

Keywords

• AChE/BuChE
• 2-hydroxy-N-phenylbenzamide derivatives
• molecular docking
• QSAR
• ADME-T
• interactions