Discovery of promising cholinesterase inhibitors for Alzheimer's disease treatment through DFT, docking, and molecular dynamics studies of eugenol derivatives

Abstract

Abstract Cholinesterase enzymes are promising drug targets for the symptomatic treatment of Alzheimer's disease. Indeed, the activity inhibition of these acetylcholine‐degrading enzymes leads to improved neurocognitive function. The present work, attempted to identify eugenol derivatives possibly capable of inhibiting the acetylcholine enzymes, by implementing density functional theory (DFT), docking and molecular dynamics methods. The investigated compounds exhibited moderate to high affinity toward the target proteins with free binding energy values ranging from −6.3 to −11.5 kcal/mol. The best ligands in terms of binding energy were evaluated for their pharmacokinetic properties. Furthermore, molecular dynamics studies were performed to assess the stability under aqueous environment of ligands having shown good pharmacokinetic properties. The obtained results revealed that 4‐alkyl‐2‐methoxyphenyl 3‐bromobenzoate strongly tended to act as dual inhibitor of Acetylcholinesterase and Butyrylcholinesterase, leading to a good alternative for the treatment of AD. The highlighting of this study can be of great support for the Alzheimer treatment development.