Abstract
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 (His447) 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.
Highlights
Alzheimer’s disease (AD) is a typical neurodegenerative condition that affects more than 46 million individuals globally [1,2,3]
In 2018, more than 16 million Americans and unpaid caregivers spent an estimated 18.5 billion hours caring for individuals with AD or another form of dementia
Tacrine formed only one hydrogen bond with Glu202. These findings suggest that indirubin and dehydroevodiamine form more stable complexes with AChE than tacrine [40,41]
Summary
Alzheimer’s disease (AD) is a typical neurodegenerative condition that affects more than 46 million individuals globally [1,2,3]. AD is a deadly neurodegenerative disease for which no preventative treatment is available [4,5,6,7]. 2017, which made it the sixth most common cause of death and the fifth most common among Americans aged ≥65 years. In 2018, more than 16 million Americans and unpaid caregivers spent an estimated 18.5 billion hours caring for individuals with AD or another form of dementia. In 2019, total expenditure on health, long-term care, and hospice facilities for people age ≥65 years with dementia was projected to be $290 billion [9]. Disturbances in cholinergic neurotransmission contribute to the memory weakness that characterizes
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