Structure-Based Molecular Docking and Molecular Dynamics Simulation of Phytoconstituents from Senecio Species as Potential Acetylcholinesterase Inhibitors Targeting Alzheimer’s Disease

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. Pathologically, AD is defined by the accumulation of neurofibrillary tangles and amyloid-β plaques, leading to neuronal cell death and dysfunction. With a significant reduction in acetylcholine levels, the disruption of the cholinergic system is an essential part of AD pathogenesis. Acetylcholine is hydrolyzed by the enzyme acetylcholinesterase (AChE), worsening the cholinergic deficiency of AD. 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 as inhibitors of acetylcholinesterase (AchE), an enzyme implicated in the etiology of Alzheimer's disease, is investigated. We identified a series of interesting compounds that could act as effective AChE inhibitors by using molecular dynamics simulation (MD) and structure-based molecular docking. These phytoconstituents exhibit strong binding affinity with AChE, like the famous drug donepezil, based on our molecular docking analysis. The MD simulations for 10–100 nanoseconds revealed that these molecules significantly stabilized proteins. Interestingly, the stability profiles for the top 1 and top 2 compounds were similar to that of donepezil but were distinct. Further inspection of solvent interaction, structural compactness, and molecular flexibility underlined the desirable interaction and dynamic stability of the top1 compound. 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.