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In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer's disease.

ABSTRACT: BACKGROUND:The N-methyl-D-aspartate (NMDA) receptors are glutamate receptors that play vital roles in central nervous system development and are involved in synaptic plasticity, which is an essential process for learning and memory. The subunit N-methyl D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter receptor in the mammalian brain. Disturbances in the neurotransmission mediated by the NMDA receptor are caused by its overexposure to glutamate neurotransmitter and can be treated by its binding to an antagonist. Among several antagonists, conantokins from cone snails are reported to bind to NMDA receptors. METHODS:This study was designed to analyze the binding mode of conantokins with NMDA receptors in both humans and rats. To study interactions, dockings were performed using AutoDock 4.2 and their results were further analyzed using various computational tools. RESULTS:Detailed analyses revealed that these ligands can bind to active site residues of both receptors as reported in previous studies. CONCLUSIONS:In light of the present results, we suggest that these conantokins can act as antagonists of those receptors and play an important role in understanding the importance of inhibition of NMDA receptors for treatment of Alzheimer's disease.

SUBMITTER: Waqar M

PROVIDER: S-EPMC5607497 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer's disease.

Waqar Maleeha M Batool Sidra S

The journal of venomous animals and toxins including tropical diseases 20170920

<h4>Background</h4>The N-methyl-D-aspartate (NMDA) receptors are glutamate receptors that play vital roles in central nervous system development and are involved in synaptic plasticity, which is an essential process for learning and memory. The subunit N-methyl D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter receptor in the mammalian brain. Disturbances in the neurotransmission mediated by the NMDA receptor are caused by its overexposure to glutamate neurotransmit ...[more]

PMID: 28943883

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Project description:UnlabelledAcetylcholine-esterase (AchE) inhibitors are one of the most potent drug molecules against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compound which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects.AimsThe aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate.Methods and materialsPhysico-chemical properties of conventional drugs and quercetin were predicted using bioinformatics tools. Molecular docking of these compounds on the active site of AchE was performed using AutoDock and comparative analysis was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR analysis.Result and discussionQuercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was -8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score -7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the molecule showed better binding affinity than parent quercetin. Quantitative structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity.ConclusionThis in silico study has conclusively predicted the superiority of the natural compound quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compound in future.

Dataset Information

In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer's disease.

Publications

In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer's disease.

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