Biocomputational Screening of Natural Compounds against Acetylcholinesterase

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of −10.03 and −9.00 kcal/mol, respectively. The key residue (His(447)) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the ‘indirubin–AChE’ interaction and three H-bonds in the ‘dehydroevodiamine–AChE’ interaction. These compounds were predicted to cross the blood–brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, ‘indirubin–AChE’ and ‘dehydroevodiamine–AChE’ complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.