Graphical abstract

Inhibition of acetylcholinesterase (AChE) is a promising treatment strategy for Alzheimer's disease (AD). Oxidative stress, inflammation and accumulation of metal ions at sites of neurodegeneration have been observed in association with AD. Flavonoids are well known for their action against inflammation and oxidative stress. Hence, they can be used for treating diseases such as AD, cancer, atherosclerosis and Parkinson's disease. Flavonols such as quercetin, myricetin, galangin, fisetin and kaempferol have been reported as inhibitors of AChE. In the present work, the enzyme inhibitory properties of morin, a flavonol, has been tested against AChE. The binding pattern of morin and 12 other flavonols at the active site of human AChE has been analyzed using molecular modeling and docking methods. In order to enhance the binding affinity of AChE for morin, in silico structural modification of the compound was carried out. The structural elements responsible for its biological functions were retained during the modification. Some of the derivatives possessed better binding energies than morin and hence they could be used as drug lead compound for the treatment of AD.

Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC(50) of NDGA on AChE was 46.2 μM. However, NDGA showed very poor central nervous system (CNS) activity and blood-brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD.