Jatamansinol from <i>Nardostachys jatamansi</i>: a multi-targeted neuroprotective agent for Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial progressive and irreversible neurodegenerative disorder characterized by severe memory impairment and cognitive disability in the middle and old-aged human population. There are no proven drugs for AD treatment and prevention. In Ayurveda, medhya plants are used to prepare Rasayana, and its consumption improves memory and cognition. <i>Nardostachys jatamansi</i> (D.Don) DC is a medhya plant used in traditional medicine to treat neurological disorders, and its unique pyranocoumarins can be a potential drug candidate for AD. Given its traditional claims, this study aims to find the multi-target potential efficacy of the ligands (drug molecules) against the AD from <i>N. jatamansi</i> pyranocoumarins using computational drug discovery techniques. Drug likeliness analysis confirms that pyranocoumarins of <i>N. jatamansi,</i> such as seselin, jatamansinol, jatamansine, jatamansinone, and dihydrojatamansin are probable drug candidates for AD. Molecular docking, molecular dynamic simulations, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis confirm that dihydrojatamansin inhibits acetylcholinesterase (<i>AChE</i>), and jatamansinol inhibits butyrylcholinesterase (<i>BuChE</i>), glycogen synthase kinase 3β <i>(GSK3β</i>), and kelch-like ECH-associating protein 1 (<i>Keap1</i>) AD therapeutic targets. Therefore, this study provides potential multi-target inhibitors that would further validate experimental studies, leading to new treatments for AD. Communicated by Ramaswamy H. Sarma