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In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies.

ABSTRACT: INTRODUCTION:Alzheimer's disease (AD) has increased at an alarming rate and is now a worldwide health problem. Inhibitors of acetylcholinesterase (AChE) leading to inhibition of acetylcholine breakdown constitute the main therapeutic strategy for AD. Psoralen was investigated as inhibitor of AChE enzyme in an attempt to explore its potential for the management of AD. MATERIALS AND METHODS:Psoralen was isolated from powdered Psoralea corylifolia fruits. AChE enzyme inhibitory activity of different concentrations of psoralen was investigated by use of in vitro enzymatic and molecular docking studies. Further, the enzyme kinetics were studied using Lineweaver-Burk plot. RESULTS:Psoralen was found to inhibit AChE enzyme activity in a concentration-dependent manner. Kinetic studies showed psoralen inhibits AChE in a competitive manner. Molecular docking study revealed that psoralen binds well within the binding site of the enzyme showing interactions such as ?-? stacking and hydrogen bonding with residues present therein. CONCLUSION:The result of AChE enzyme inhibitory activity of the psoralen in this study is promising. It could be further explored as a potential candidate for further development of new drugs against AD.

SUBMITTER: Somani G

PROVIDER: S-EPMC4333625 | biostudies-literature | 2015 Jan-Mar

REPOSITORIES: biostudies-literature

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In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies.

Somani Gauresh G Kulkarni Chinmay C Shinde Prashant P Shelke Rupesh R Laddha Kirti K Sathaye Sadhana S

Journal of pharmacy & bioallied sciences 20150101 1

<h4>Introduction</h4>Alzheimer's disease (AD) has increased at an alarming rate and is now a worldwide health problem. Inhibitors of acetylcholinesterase (AChE) leading to inhibition of acetylcholine breakdown constitute the main therapeutic strategy for AD. Psoralen was investigated as inhibitor of AChE enzyme in an attempt to explore its potential for the management of AD.<h4>Materials and methods</h4>Psoralen was isolated from powdered Psoralea corylifolia fruits. AChE enzyme inhibitory activ ...[more]

PMID: 25709334

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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models afforded R (2), [Formula: see text] and [Formula: see text] values in ranges of 0.66-0.93, 0.55-0.79 and 0.56-0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R (2), [Formula: see text] and [Formula: see text] values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard-Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds 13, 5 and 28 exhibited the lowest binding energies of -12.2, -12.0 and -12.0 kcal/mol, respectively, against human AChE, which is modulated by hydrogen bonding, π-π stacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors.

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In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies.

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In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies.

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