Etonogestrel and Alzheimer's: A multi-scale computational approach to acetylcholinesterase inhibition

This study explores Etonogestrel, a synthetic progestin used in hormonal contraceptives, as a potential Acetylcholinesterase (AChE) inhibitor for treating Alzheimer's disease. The study involved analyzing Etonogestrel's molecular properties, preparing AChE macromolecules, and conducting molecular docking and dynamics simulations. Techniques like MM-GBSA, dynamic cross-correlation matrix, and principal component analysis were used to assess Etonogestrel's interaction with AChE. Etonogestrel demonstrated a strong binding affinity to AChE, primarily through van der Waals and pi-interactions. Molecular dynamics simulations indicated a stable binding mode, suggesting Etonogestrel's potential as a reversible AChE inhibitor. The findings suggest that Etonogestrel might have promising cognitive-enhancing properties through its interaction with AChE. However, the study emphasizes the need for experimental validation to confirm its therapeutic efficacy and safety. • Etonogestrel showed reversible AChE inhibition via van der Waals and pi-interactions. • MD simulations confirmed stable Etonogestrel–AChE binding over a 200 ns trajectory. • MM-GBSA revealed hydrophobic interactions as key contributors to Etonogestrel–AChE binding. • PCA and DCCM indicated Etonogestrel stabilized AChE structure and functional dynamics. • ADMET profile showed good pharmacokinetics and low toxicity for Alzheimer’s repurposing.