Contemporary literature documents
extensive research on common
causative mechanisms, pathogenic pathways and dual effective remedies
for Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM).
Tolbutamide (TBM), chlorpropamide (CPM), and glyburide (GLY) are three
sulfonylurea antidiabetic drugs of different generations. All these
drugs were found to exhibit moderate to strong inhibitory efficiency
on the neurotransmitter degrading enzyme acetylcholinesterase (AChE)
with GLY (IC50 = 0.74 ± 0.02 μM) being the most
potent, followed by CPM (IC50 = 5.72 ± 0.24 μM)
and TBM (IC50 = 28.9 ± 1.60 μM). Notably, the
inhibition efficiency of GLY is even comparable with the FDA approved
AD drug, donepezil (DON). The larger size of GLY spans almost the
full gorge of AChE ranging from catalytic active site (CAS) to the
peripheral active site (PAS) with relatively strong binding affinity
(6.0 × 105 M–1) and acts as a competitive
inhibitor for AChE. On the other hand, while they show relatively
weak binding ((2–6) × 104 M–1), both CPM and TBM act as noncompetitive binders. While these two
drugs can bind to PAS, MD simulation results predict an alternative
noncompetitive inhibition mechanism for CPM. These results open the
possibility of repurposing the antidiabetic drugs, particularly GLY,
in the treatment of AD. The consequential side effect of excess acetylcholine
production, due to the administration of these drugs to AD-unaffected
patients, can be rectified by using colloidal gold and silver nanofluids
as potential AChE activity boosters.
The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of non-competitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC = 48.49 ± 5.6 nM) than the reference drug DON (IC = 74.13 ± 8.3 nM), unequivocally amplifying its importance. The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin. The mechanism of inhibition remained impervious when the experimental medium was switched from aqueous buffer to HSA, albeit noticeable change in the inhibition potency of the compound 3, 3'- Methylene-bis (4-hydroxy coumarin) (MHC) (38%) and CC (35%). Both the coumarin derivatives were observed to bind to the peripheral anionic site (PAS) of AChE and also found to displace the fluorescence marker thioflavinT (ThT) from AChE binding pocket. All experimental observations were seconded by molecular docking and MD simulation results. The inferences drawn in this study form a foundation for further investigation on these compounds; magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.
Conformational alterations in the structure of deoxyribonucleic acid (DNA) due to oxidative stress in the DNA backbone are known to be at the root of many life-threatening diseases. Clear comprehension...
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