In silico discovery of noteworthy multi-targeted acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a multifactorial and fatal neurodegenerative disorder. Memory loss and cognitive decline occur due to death of brain cells. Various important hallmarks of AD have reported like deposition of β-amyloid fibril, β-amyloid oligomers formation, hyperactive phosphorylated tau protein, oxidative stress in cell, low levels of acetylcholine, etc. Treatment of AD based on cholinesterase inhibitors is only symptomatic, its efficacy is limited. A multi-targeted ligand may enable therapeutic efficacy, because of being multifactorial nature of AD. Hence, this research has been focused on developing novel components that preferentially block cholinesterase and simultaneously bind with other targets like β-secretase, Monoamine oxidases, Glycogen synthase kinase, etc., which are directly or indirectly associated with AD to offer more efficient treatment than earlier. To select novel targets and therapeutic ligands, computational approaches have proved to be robust and reliable tools. To expose intermolecular binding mode of the compounds, molecular docking studies and molecular dynamics simulation studies performed and the results indicate their substantial interactions with the active sites of AChE and BCHE and other responsible targets. In silico ADME/T, study performed to estimate several pharmacokinetic parameters and toxicity profile of the selected compounds. Amongst the series, compounds 2-(2,2-dimethylchromen-6-yl)-5,7- dihydroxychromen-4-one (PCID5315395) and 7-(1,3-benzodioxol-5-yl)-5-hydroxy-2,2-dimethylpyrano [3,2-g] chromen-6-one (PCID5983661) are the most encouraging multi-targeted candidates which have the ability to increase memory, acetylcholine as well as other neurotransmitter levels and give the protection of the neurons against the cognitive deficit. In this study, we are proposing two new compounds from PubChem database as AChE as well as BCHE, MAO-A, MAO-B, Beta-secretase, GSK-3 and N-Methyl-D-aspartate (NMDA) inhibitors for further investigation and experimental validation.