Unveiling the Pharmacological Potential of Hypericum perforatum Derived Compounds against Alzheimer’s Disease: Insights from Computational and Dynamics Studies

The worldwide health care system is significantly threatened by Alzheimer's disease (AD), which arises from a combination of conditions leading to neuronal malfunction, memory impairment, and cognitive decline. Hypericum perforatum, often known as St. John's wort, has garnered significant attention due to its possible therapeutic advantages in the treatment of neurodegenerative diseases. The lack of efficacious treatments for diseases such as Alzheimer's and Parkinson's disease is becoming a growing global health issue. This study investigated the therapeutic potential of five reported phytochemicals of this plant including hypericin (HP-1), biapigenin (HP-2), kaempferol (HP-3), hyperforin (HP-4), hyperocide (HP-5), based on their binding affinity with AD-associated proteins namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The Glide-XP module from Schrödinger was utilized to conduct thorough docking investigations, which were then followed by molecular dynamic (MD) simulations using IMods. The selected compounds were subjected to docking analysis to determine the binding energies of their interactions with the target proteins. Additionally, molecular dynamics (MD) simulations were conducted to confirm the stability of the bound complexes. The top hits among the five selected phytochemical compounds, HP-2 (-7.461 kcal/mol) and HP-1 (-7.304 kcal/mol), have the greatest docking scores for the AChE enzyme. Similarly, in case of BChE enzyme, the phytochemicals HP-5 (-7.991 kcal/mol) and HP-3 (-7.849 kcal/mol) have substantial binding affinities. Through the different online tools including swissADME, pkSCM, stoptox, molinspiration, and swiss target prediction analysis, the selected compounds’ pharmacokinetic characteristics, drug likeness, toxicity, bioactivity score prediction, and enzyme target prediction were also examined.