In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer\u2019s disease

Maleeha Waqar,Sidra Batool

doi:10.1186/s40409-017-0132-9

Abstract

BackgroundThe 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.MethodsThis 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.ResultsDetailed analyses revealed that these ligands can bind to active site residues of both receptors as reported in previous studies.ConclusionsIn 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.

Highlights

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
Structure prediction and validation of NMDA receptors (NMDAR) in human The predicted three-dimensional structure of the NMDA receptor in humans was superimposed on Chimera with its template, a NMDA receptor in rat yielding a root mean square deviation (RSMD) of 0.181 Å
Conantokins had been reported as selective antagonists of N-methyl D-aspartate receptor subtype 2B (NR2B) subtype of the NMDA receptor

Summary

Introduction

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. The NMDA receptors (NMDAR) play vital roles in central nervous system (CNS) development [2] These receptors are highly permeable to Ca2+ ions and the calcium flux is critically important for synaptic plasticity, which is an essential neurochemical process for learning and memory [2,3,4]. The subunit N-methyl-D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter. The excessive stimulation by the glutamate neurotransmitter of neurons causes excitotoxicity and

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