Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Devashree N. Patil, Sushama A. Patil, Srinivas Sistla, Jyoti P. Jadhav, David A. Lightfoot.
Among neurodegenerative diseases, Alzheimer’s disease (AD) is one of the most grievous disease. The oldest cholinergic hypothesis is used to elevate the level of cognitive impairment and acetylcholinesterase (AChE) comprises the major targeted enzyme in AD. Thus, acetylcholinesterase inhibitors (AChEI) constitutes the essential remedy for the treatment of AD. The study aims to evaluate the interactions between natural molecules and AChE by Surface Plasmon Resonance (SPR). The molecules like alkaloids, polyphenols and substrates of AChE have been considered for the study with a major emphasis on affinity and kinetics. To better understand the activity of small molecules, the investigation is supported by both experimental and theoretical approach such as fluorescence, Circular Dichroism (CD) and molecular docking studies. Amongst the screened ones tannic acid showed promising results compared with others. The methodology followed here have highlighted many molecules with a higher affinity towards AChE and these findings may take lead molecules generated in preclinical studies to treat neurodegenerative diseases. Additionally, we suggest a unique signature for the heterogeneous analyte model using competitive experiments for analyzing simultanous interactions of both the analytes.
Alzheimer’s disease is the global age-related neurodegenerative disease which depicts 50–75 percentage (%) of the population of dementia all over the globe . It is associated with behavioral changes, cognitive dysfunction, progressive memory deterioration and difficulty in daily living . AD is marked by depletion of cholinergic synapses in the hippocampus and neocortex, resulting in insufficiency of the neurotransmitter acetylcholine (ACh).
New research is emerging on the role of cholinergic drugs in the treatment of many other diseases like dementia , multiple sclerosis , tobacco and alcohol usage disorder [40,41] nausea, opioid use disorder or opioid overdosage and cocaine addiction . Anticholinergic drugs or inhibitors differ in their pharmacological profile and warrants more research into their dosing, PK (Pharmacokinetic), PD (Pharmacodynamic) and considerable side effects . Mainly AChEI is also used clinically for the treatment of various diseases like glaucoma, myasthenia gravis and Lewy body dementia. For the effective treatment, potent inhibitors must bind to the active site of the enzyme reversibly, as irreversible binding may cause severe consequences, eventually loss of receptor activity and significant toxicological effects . Hence, reversible AChE inhibitors have become the increasingly central role for the treatment of AD. Also, natural molecules and plant secondary metabolites are found to be superior in their inhibiting potential compared to synthetic molecules . Nowadays, research is mainly focussed on natural molecules from plants as prominent sources of new or rather more effective AChEI. Hence, in present study, the screening of binding kinetics and competitive studies of various natural small molecules against AChE enzyme have been evaluated. Whereas, the previous studies were available only on the synthetic drug molecules inhibiting AChE. But comparatively very few studies have been reported on the characterization and dosing of inhibitors by using SPR.