Coumarin compounds against Alzheimer's disease: An in-silico approach

Alzheimer's disease, one of the most common causes of senile dementia, has no cure which makes the development of new treatments crucial. In this regard, secondary metabolites from plants have shown important bioactivity, including the inhibitory effect against acetylcholinesterase enzyme (AChE). An important group of such metabolites are coumarins, in particular the 7-hydroxycoumarin and its derivatives. These molecules have a wide variety of biological activities as antioxidants, anti-neurodegenerative and anti-Alzheimer drugs. In this study, eight coumarin derivatives were analyzed by means of ADMET properties, molecular docking and molecular dynamics simulations. Out of our set of derivatives, four coumarin compounds showed better docking scores (−11.60 to - 12.07 kcal/mol) than the reference molecule donepezil, one of the drugs of first-line in the treatment of the disease as a reversible inhibitor of AChE. According to molecular dynamics simulations, the top selected compounds ( Cou2 , Cou5 , Cou6 and Cou8 ) displayed interactions with amino acids from the binding site of AChE as potential multisite inhibitors, maintaining its interaction during the simulation time. The studied coumarins showed a biological activity as anti-inflammatory and free radical scavenger, regarding in silico predictions. All coumarins had good physicochemical and pharmacokinetic predicted parameters, thus positioned them as potential candidates to prove as Alzheimer's disease drugs by in vitro and in vivo evaluations. • Coumarin compounds are potential molecules for Alzheimer's disease by interacting with acetylcholinesterase enzyme (AChE). • Multisite inhibitors of AChE are good candidates for Alzheimer's treatment since they can inhibit acetylcholine hydrolyzation and Aβ deposition and aggregation. • Coumarin compounds presented best docking scores at the binding site of AChE than donepezil, a drug used for Alzheimer's disease. • Molecular dynamics simulations of protein-ligand complexes, predicted by molecular docking calculations, revealed that the coumarin compounds can interact at the binding site through simulation time. • Coumarins have good intestinal absorption, bioavailability, liver metabolism mediated by enzymes such as cytochrome P450, as well as low potential for toxicity and an adequate elimination.