2D-QSAR and Molecular Docking based virtual screening of the herbal molecules against Alzheimers Disorder: An approach to predict CNS activity

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimers Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of synthetic and herbal molecules, however, the majority of them failed to reproduce the results in preclinical or clinical settings. To address these issues, we developed a 2D-QSAR model that could not only efficiently predict the AChE inhibitory activity of herbal molecules but also predicted their potential to cross BBB to exert their beneficial effects during AD. Applying this model, virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the CNS for being beneficial for the management of AD, we determined a CNS PPO score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.