Structure-based molecular docking and molecular dynamics simulation of phytoconstituents from Senecio species as potential acetylcholinesterase inhibitors targeting Alzheimer's disease.

UNLABELLED: Alzheimer's disease (AD) is a neurodegenerative condition most often occurring in aged individuals and displaying symptoms of memory impairment, cognitive decline, and behavioral disturbances. With a significant reduction in acetylcholine levels, the disruption of the cholinergic system is an essential part of AD pathogenesis. By increasing the availability of acetylcholine and thus enhancing cholinergic transmission, acetylcholinesterase inhibitors (AChEIs) like galantamine, donepezil, and rivastigmine are employed to alleviate symptoms. In this study, the prospect of phytoconstituents of Senecio species collected from various literature (GC-MS and LC-MS data) as inhibitors of acetylcholinesterase (AchE) is investigated. A total of 250 compounds were screened for ADMET using SwissADME database. Out of these 42 were eligible for the docking study. The docking results revealed that 2 compounds (Piperitol [4EY7-PIP]) and (4R)-4-hydroxy-4,5,5-trimethyl-3-[(E)-3-oxobut-1-enyl]cyclohex-2-en-1-one [xxx]) showed stronger binding to the AchE receptor than the standard drug, donepezil. Further, the compounds were subjected to Molecular dynamics simulations for 100ns. The results revealed that these molecules significantly stabilized proteins in different parameters, such as RMSD, RMSF, Rg, SASA, and MM-PBSA. The inspection of solvent interaction, structural compactness, and molecular flexibility underlined the desirable interaction and dynamic stability of 4EY7-PIP. Steered Molecular Dynamics (SMD) uses externally applied forces to probe molecular interactions, conformational changes, and energy landscapes beyond the reach of conventional MD. Based on these findings, Senecio species most prominent phytoconstituent can be employed as a therapeutic agent against Alzheimer's disease, but more experimental studies are required to establish its value and therapeutic benefits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00556-0.