Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

Acetylcholinesterase (AChE) plays an important role in Alzheimer's disease (AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, anti-AChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic (MD) simulations; and absorption, distribution, metabolism, and excretion (ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of −12.335 with a good binding energy value of −73.313 kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30 ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies. Keywords: Alzheimer's disease, Acetylcholinesterase, Phytocompounds, Molecular docking, Free energy calculations, Molecular dynamic simulations