Alzheimer’s disease, characterized by a decline in cognitive functions, is frequently associated with decreased levels of acetylcholine due to the overactivity of acetylcholinesterase (AChE). Inhibiting AChE has been a key therapeutic strategy in treating Alzheimer’s disease, yet the search for effective inhibitors, particularly from natural sources, continues due to their potential for fewer side effects. In this context, three new alkaloids—oleracone L, portulacatone B, and portulacatal—extracted from Portulaca oleracea L., have recently shown promising anticholinesterase activity in vitro. However, no experimental or computational studies have yet explored their binding potential. This study represents the first comprehensive in silico analysis of these compounds, employing ADME prediction, molecular docking, molecular dynamics simulations, and MM-PBSA calculations to assess their therapeutic potential. The drug-likeness was evaluated based on Lipinski, Pfizer, Golden Triangle, and GSK rules, with all three alkaloids meeting these criteria. The ADME profiles suggested that these alkaloids can effectively cross the blood–brain barrier, a critical requirement for Alzheimer’s treatment. Molecular docking studies revealed that oleracone L had the highest binding affinity (−10.75 kcal/mol) towards AChE, followed by portulacatal and portulacatone B, demonstrating significant interactions with crucial enzyme residues. Molecular dynamics simulations over 200 ns confirmed the stability of these interactions, with RMSD values below 2 Å for all complexes, indicating stable binding throughout the simulation period. RMSF and the radius of gyration analyses further corroborated the minimal impact of these alkaloids on the enzyme’s overall flexibility and compactness. Moreover, MM-PBSA calculations provided additional support for the binding efficacy, showing that oleracone L, with the most favorable binding energy, could be a superior inhibitor, potentially due to its stronger and more consistent hydrogen bonding and favorable electrostatic interactions compared to the other studied alkaloids. These computational findings highlight the binding efficiency and potential therapeutic viability of these alkaloids as AChE inhibitors, suggesting they could be promising candidates for Alzheimer’s disease treatment. The study underscores the importance of further validation through in vitro and in vivo experiments to confirm these predictions.
