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

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.

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“…Portanto, os antagonistas de NMDAR surgiram como potenciais compostos para pacientes com DA uma vez que o receptor em si tem muitas subunidades e suas variantes têm inúmeras funções cerebrais. Vale resaltar ainda que a subunidade NMDA do subtipo de receptor 2B (NR2B) é o principal receptor do neurotransmissor excitatório no cérebro de mamíferos 53 .…”

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“…W al. built a homologue model of the 3D structure of NMADR based on the structu rat NMDAR (PDB#3JPW) and analyzed by molecular docking the affinity of sev nantokins towards this target [38]. Moreover, most of the compounds interacted w idues Gln110 and Glu236, in the NR2B subunit of the NMDAR, and with Ile111, and Pro177 by hydrophobic interactions [38].…”

“…The main residues in the NMDAR active site are His88, Ser114, Thr116, Art121, Gly172, Ser173, Thr174, and Tyr214, of which the predicted compound HTS 00987 (Figure 5) interacts with His88, Thr174, and Tyr214, while memantine was not predicted to interact with none of these residues, indicating a potential pharmacological interest of this compound [37]. Waqar et al built a homologue model of the 3D structure of NMADR based on the structure of the rat NMDAR (PDB#3JPW) and analyzed by molecular docking the affinity of several conantokins towards this target [38]. Moreover, most of the compounds interacted with residues Gln110 and Glu236, in the NR2B subunit of the NMDAR, and with Ile111, Phe114, and Pro177 by hydrophobic interactions [38].…”

“…Waqar et al built a homologue model of the 3D structure of NMADR based on the structure of the rat NMDAR (PDB#3JPW) and analyzed by molecular docking the affinity of several conantokins towards this target [38]. Moreover, most of the compounds interacted with residues Gln110 and Glu236, in the NR2B subunit of the NMDAR, and with Ile111, Phe114, and Pro177 by hydrophobic interactions [38]. A similar binding pattern was observed for the rat crystal structure, indicating that conankotins might be potential NMDAR antagonists [38].…”

“…Moreover, most of the compounds interacted with residues Gln110 and Glu236, in the NR2B subunit of the NMDAR, and with Ile111, Phe114, and Pro177 by hydrophobic interactions [38]. A similar binding pattern was observed for the rat crystal structure, indicating that conankotins might be potential NMDAR antagonists [38]. In another study carried out by Hu and co-workers, the affinity of several tetramethylpyrazine derivatives, with known NMDAR antagonist activity, was studied towards its catalytic site (PDB#5UOW) by molecular docking [39].…”